CN112574235B - RET inhibitor, pharmaceutical composition and application thereof - Google Patents

RET inhibitor, pharmaceutical composition and application thereof Download PDF

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CN112574235B
CN112574235B CN202011031902.3A CN202011031902A CN112574235B CN 112574235 B CN112574235 B CN 112574235B CN 202011031902 A CN202011031902 A CN 202011031902A CN 112574235 B CN112574235 B CN 112574235B
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ring
independently
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ret
compound
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CN112574235A (en
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谢洪明
罗明
张英俊
杨桂珍
王凯
贾媛媛
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention belongs to the field of medicines, and relates to a RET inhibitor, a pharmaceutical composition thereof and application thereof. In particular, the present invention relates to a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound of formula (I), to pharmaceutical compositions comprising said compounds, and to the use of said compounds and pharmaceutical compositions thereof in the manufacture of a medicament, in particular for the treatment and prevention of diseases and disorders associated with useful RET, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

Description

RET inhibitor, pharmaceutical composition and application thereof
Technical Field
The present invention is in the field of medicaments, in particular, the present invention relates to novel compounds exhibiting a transfection-phase Rearrangement (RET) kinase inhibition, pharmaceutical compositions comprising said compounds, the use of compounds or pharmaceutical compositions thereof in the manufacture of a medicament, in particular for the treatment and prevention of RET related diseases and disorders, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
Background
Transfection rearrangement (Re-arranged during transfection, RET) is one of the receptor-type tyrosine kinases belonging to the cadherin superfamily that activates a number of downstream pathways involved in cell proliferation and survival.
The consequences of abnormal RET gene production (point mutations, chromosomal translocations, chromosomal inversion, gene amplification) are reported to be related to canceration. RET fusion proteins are associated with several cancers, including papillary thyroid cancers and non-small cell lung cancers. RET fusion proteins are identified as driving factors for certain cancers, which motivates the use of multi-kinase inhibitors with RET inhibiting activity to treat patients whose tumors express RET fusion proteins. Multiple kinase inhibitors such as Sorafenib (Sorafenib), sunitinib, vandetanib, and pluratinib have been reported to exhibit cell proliferation inhibition (J Clin Oncol 30,2012,suppl;Abstract no:7510) on KIF5B-RET expressing cell lines. In addition, the multi-kinase inhibitor cabotinib was reported to exhibit partial efficacy in two patients with non-small cell lung Cancer positive for RET fusion gene (Cancer discover, 3 (6), jun 2013, p.630-5). However, these drugs cannot always be administered at a level sufficient to inhibit RET due to toxicity resulting from inhibition of targets other than RET. Furthermore, one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Kinase reactivation via mutation is a common drug resistance mechanism. When resistance occurs, the treatment options for patients are often very limited and in most cases cancer progression is not inhibited. WO 2017011776 discloses single-target RET kinase inhibitors which have good preventive or therapeutic effects on RET and its mutation-related cancers. There is still a need to further develop compounds that inhibit RET and its resistant mutants to cope with cancers associated with abnormal RET genes.
Disclosure of Invention
The invention provides a novel compound for inhibiting a transfection-phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutants and good inhibition selectivity on RET wild type and RET gene mutants.
The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can contribute to a reduction in side effects, an expansion of therapeutic index, or an improvement in tolerability, etc.
In one aspect, the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
wherein,
X 1 、X 2 、X 3 、X 4 and X 5 Each independently is CR 4 Or N;
y is O, NH or S;
t is a bond, alkylene-O-alkylene or alkylene-NH-, and said T is optionally selected from the group consisting of 1, 2, 3 or 4 of D, OH, F, cl, br, I, CN, NH 2 Substituted with alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, or alkylamino;
Ring G is a bridged carbocyclyl or bridged heterocyclyl;
q is 0, 1, 2, 3 or 4;
R a is D, OH, NH 2 、F、Cl、Br、I、CN、NR 5 R 6 、OR 7 、-NR 6 C(＝O)R 7 、-S(＝O) 2 R 7 、-S(＝O)R 7 、-C(＝O)R 7 、-C(＝O)OR 7 Oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl;
e is a bond、-NR 6 -or-O-;
ring A is a bridged, fused or spiro-subunit, and ring A is optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and heterocyclylalkyl substituents;
q is a bond, - (CR) 2 R 3 ) t O-、-(CR 2 R 3 ) f -、-(CR 2 R 3 ) t -NR 6 -、-(C＝O)(CR 2 R 3 ) t -、-(C＝O)(CR 2 R 3 ) t -(S＝O) 2 (CR 2 R 3 ) f -、-(C＝O)(CR 2 R 3 ) t -NR 6 (CR 2 R 3 ) f -、-(C＝O)(CR 2 R 3 ) t -O(CR 2 R 3 ) f -、-(C＝O)NR 6 O(CR 2 R 3 ) f -、-(S＝O) 2 -NR 6 -(CR 2 R 3 ) t -、-(CR 2 R 3 ) f -(C＝O)-、-(CR 2 R 3 ) t -(C＝O)-NR 6 -(CR 2 R 3 ) t -、-(S＝O) 2 (CR 2 R 3 ) t -、-(CR 2 R 3 ) f -(S＝O) 2 (CR 2 R 3 ) t -、-(S＝O) 2 O-、-O(C＝O)-、-(C＝O)NR 6 -or-NR 6 (C＝O)-；
Each f is independently 1, 2, 3 or 4;
each t is independently 0, 1, 2, 3 or 4;
m is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally substituted with 1, 2, 3 or 4 groups selected from D, F, cl, CN, OH, NR 5 R 6 、OR 7 Alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl andsubstituted cycloalkyl;
R 1 h, D, CN, F, cl, br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2);
each R is 2 And R is 3 OH, F, H, D, CN, cl, br, NH independently 2 Hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;
or, R 2 、R 3 And the same C atom attached thereto forms a carbocyclic or heterocyclic ring;
R 4 h, D, F, cl, br, alkyl or alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2);
R 5 is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein each of said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, NH 2 Substituted with substituents such as alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
R 6 is H, D, alkyl or alkoxyalkyl, wherein each of said alkyl and alkoxyalkyl is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2);
R 7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In some embodiments, T is a bond, C 1-6 Alkylene, C 1-6 alkylene-O-, C 1-6 alkylene-O-C 1-6 Alkylene or C 1-6 alkylene-NH-and T is optionally selected from D, OH, F, cl, br, I, CN, NH by 1, 2, 3 or 4 2 、C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-12 membered heteroaryl and C 1-6 The substituents of the alkylamino groups are substituted.
In some embodiments, T is a bond, -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 2 -O-、-(CH 2 ) 2 -O-CH 2 -or- (CH) 2 ) 2 -NH-, and said T is optionally selected from the group consisting of 1, 2, 3 or 4 of D, OH, F, cl, br, I, CN, NH 2 、CF 3 、CHF 2 、CHCl 2 Substituted with methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino and dimethylamino.
In some embodiments of the present invention, in some embodiments,
ring G is a 6-12 membered bridged carbocyclyl or a 6-12 membered bridged heterocyclyl;
R a is D, OH, NH 2 、F、Cl、Br、I、CN、NR 5 R 6 、OR 7 、-NR 6 C(＝O)R 7 、-S(＝O) 2 R 7 、-S(＝O)R 7 、-C(＝O)R 7 、-C(＝O)OR 7 Oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 A hydroxyalkyl group;
R 5 h, D, C of a shape of H, D, C 1-6 Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, NH 2 、C 1-6 Alkylamino, C 1-6 Alkyl, C 1-6 Alkylsulfonic acidsAcyl, C 1-6 Alkoxy, C 6-10 Substituents for aryl and 5-10 membered heteroaryl;
R 6 h, D, C of a shape of H, D, C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 Alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2);
R 7 is OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl.
In some embodiments, ring G is of the following sub-structural formula:
wherein,
each Z is 1 Independently CH or N; and
each Z is 2 Independently CH 2 C= O, NH, O, S, S = (O) or s= (O) 2 -。
In some embodiments, ring G is of the following sub-structural formula:
R a is D, OH, NH 2 、F、CF 3 、CHCl 2 、CHF 2 、CH 2 F、CF 3 CH 2 、Cl、Br、I、CN、NH 2 、NHCH 3 、N(CH 3 ) 2 、-NHC(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O)CH 3 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OC(CH 3 ) 3 Oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl;
R 5 h, D is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl or pyrazolyl; wherein said methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, NH 2 Methyl, -S (=o) 2 CH 3 Substituents of methoxy, ethoxy and phenyl;
R 6 is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently and optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2);
R 7 is OH, methyl, ethyl or NH 2 、N(CH 3 ) 2 Methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
In some embodiments, ring A is a 5-12 membered bridged ring, a 5-12 membered fused ring, or a 5-12 membered spiro ring, and ring A is optionally substituted with 1, 2, 3, or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments, ring a is of the following sub-structural formula:
wherein each Z 1a And Z 2a Independently CH 2 Or NH;
each Z is 3a And Z 7a Independently CH or N;
Z 4a o, S or NH;
Each Z is 5a And Z 6a Independently CH 2 、O、S、S(＝O)、S(＝O) 2 C (=o) or NH;
each m and t is independently 0, 1 or 2;
each n and t1 is independently 0 or 1;
wherein each sub-structural formula of ring A is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments, ring a is of the following sub-structural formula:
wherein each sub-structural formula of ring A is independently optionally substituted with 1, 2,3 or 4 are selected from F, cl, br, OH, oxo, NH 2 、NHCH 3 、CH 3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 Substituents selected from the group consisting of hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, M is H, D, a 5-10 membered heteroaryl, C 6-10 Aryl, C 3-7 Cycloalkyl or 3-12 membered heterocyclyl; and M is optionally selected from D, F, cl, CN, OH, NR by 1, 2, 3 or 4 5 R 6 、OR 7 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 6-10 Aryl, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 1-6 Alkanoyl, 3-7 membered heterocyclyl and C 3-7 The substituents of cycloalkyl groups are substituted.
In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1]Heptyl, hexahydrofuro [3,4-c ]]Pyrrolyl, 3-azabicyclo [3.1.0]Hexalkyl octahydropyrrolo [1,2-a ]]Pyrazinyl or 5-azaspiro [2.4 ]]A heptyl group; and M is optionally selected from D, F, cl, CN, OH, CF by 1,2, 3 or 4 3 、CHCl 2 、CHF 2 、CH 2 F、CF 3 CH 2 、NH 2 、NHCH 3 、N(CH 3 ) 2 Substituted with a trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl group;
In some embodiments, R 1 H, D, CN, F, cl, br, methyl, ethyl or cyclopropyl, wherein said methyl, ethyl and cyclopropyl are independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2);
R 4 h, D, F, cl, br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups may independently optionally be substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, each R 2 And R is 3 OH, F, H, D, CN, cl, br, NH independently 2 、C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl;
or, R 2 、R 3 And the same carbon atom to which it is attached form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
In some embodiments, each R 2 And R is 3 Independently OH, F, CF 3 、CHCl 2 、CHF 2 、H、D、CN、Cl、Br、NH 2 Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH) 3 ) 2 Methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridinyl or pyrazinyl;
Or, R 2 、R 3 And the same carbon atom to which it is attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
In some embodiments, Q is a bond, -O-, - (CH) 2 ) 2 O-、-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH(CH 3 )CH 2 NHCH 2 -、-(C＝O)OC(CH 3 ) 2 CH 2 -、-(C＝O)(CH 2 ) 2 (S＝O) 2 CH 2 -、-(C＝O)CH(OH)-、-(C＝O)CH(OH)CH 2 -、-(C＝O)-、-(S＝O) 2 -、-(C＝O)CH 2 CH(OH)-、-(C＝O)CH 2 -、-(C＝O)CH(CH 2 OH)-、-(C＝O)C(CH 3 ) 2 -、-(C＝O)CH 2 NHC(CH 3 ) 2 CH 2 -、-(C＝O)CH 2 CH(N(CH 3 ) 2 )-、-(C＝O)(CH 2 ) 2 N(CH 3 )CH 2 -、-(C＝O)C(CH 3 ) 2 CH 2 -、-(C＝O)C(OH)(CH 3 )CH 2 -、-(C＝O)CH 2 OCH 2 -、-(C＝O)(CH 2 ) 3 -、-(C＝O)CH(NH 2 )-、-(C＝O)(CH 2 ) 3 N(CH 3 )CH 2 -、-(C＝O)(CH 2 ) 2 -、-(C＝O)CH 2 CH(OH)CH 2 -、-(C＝O)CF 2 CH 2 -、-(C＝O)CH(OH)C(CH 3 ) 2 CH 2 -、-(C＝O)CH 2 C(CH 3 ) 2 CH 2 -、-(C＝O)CH 2 C(CH 3 )(OH)CH 2 -、-(S＝O) 2 CH 2 -、-(S＝O) 2 CH 2 C(CH 3 ) 2 CH 2 -、-(C＝O)CH(OCH 3 )-、-(C＝O)NHCH(CH 2 OH)(CH 2 ) 2 -、-(C＝O)NH-、-(C＝O)N(CH 3 )-、-(C＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-(C＝O)N(CH 2 CH 3 )(CH 2 ) 2 -、-(C＝O)NHC(CH 3 ) 2 CH 2 -、-(C＝O)N(CH 3 )(CH 2 ) 2 -、-(C＝O)NHCH 2 CH(CH 3 )CH 2 -、-(C＝O)NHCH 2 -、-(C＝O)NH(CH 2 ) 2 OCH 2 -、-(C＝O)N(CH 3 )(CH 2 ) 2 OCH 2 -、-(S＝O) 2 NHC(CH 3 ) 2 CH 2 -、-CH 2 CH(OH)C(CH 3 ) 2 CH 2 -、-CH(CH 3 )CH(OH)-、-CH 2 (C＝O)NHCH(CH 3 )CH 2 -、-CH 2 (C＝O)-、-(CH 2 ) 2 (C＝O)N(CH 3 )CH 2 -、-CH 2 CH(OH)-、-CH 2 CH(OH)CH 2 -、-CH 2 CH(OH)CH(CH 3 )CH 2 -、-(C＝O)CH(N(CH 3 ) 2 )-、-(C＝O)C(CH 3 ) 2 CH 2 OCH 2 -、-(C＝O)C(OCH 3 )(CF 3 )-、-(CH 2 ) 3 S(＝O) 2 CH(CH 3 )CH 2 -、-(C＝O)N(CH 2 CH 2 OCH 3 )CH 2 CH(OCH 3 )-、-CH 2 CH(OCF 3 )-、-CH 2 CH(OCH(CH 3 ) 2 )-、-CH 2 CH(OC(CH 3 ) 3 )-、-CH 2 CF 2 -、-CH(CH 3 )-、-CH 2 CH(OCH 3 )C(CH 3 ) 2 -、-CH 2 CH(N(CH 3 ) 2 )-、-NH-、-(C＝O)NHOCH 2 -、-(C＝O)NHOCH 2 (CHOH)-、-(S＝O) 2 (CH 2 CH 3 )-、-(S＝O) 2 O-、-(S＝O) 2 -NHC(CH 3 ) 2 -、-(CH 2 ) 2 (S＝O) 2 -、
In some embodiments, the compounds of the present invention have the structure of formula (I-1), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-1),
wherein,
ring A1 is of the sub-structural formula:
wherein each Z 1a And Z 2a Independently CH 2 Or NH;
and each sub-structural formula of ring A1 is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments, ring A1 is of the formula:
wherein each sub-structural formula of ring A1 is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NH 2 、NHCH 3 、CH 3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 Substituents selected from the group consisting of hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, the compounds of the present invention have the structure of formula (I-3) or (I-4), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-3) or (I-4),
wherein each Z 1 、Z 2 、Z 3a And Z 7a Independently CH or N;
each m and t is independently 0, 1 or 2;
each n and t1 is independently 0 or 1;
each of which isIndependently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments of the present invention, in some embodiments,the following sub-structural formula is shown as follows:
the following sub-structural formula is shown as follows:
wherein the method comprises the steps ofIs independently optionally substituted with 1, 2, 3 or 4 groups selected from FCl, br, OH, oxo, NH 2 、NHCH 3 、CH 3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 Substituents selected from the group consisting of hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable adjuvant.
In another aspect, the invention also provides the use of the compound of the invention or the pharmaceutical composition of the invention in the preparation of a medicament for preventing or treating RET-related diseases.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of RET-related disorders.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a method of preventing or treating RET-related disorders comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I), (I-1), (I-2) or (I-3).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (I-1), (I-2) or (I-3).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.
In particular, salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological use, in relation to the other components that make up the formulation and the mammal being treated.
Salts of the compounds of the present invention also include salts of the isolated enantiomers of the compounds of formula (I), (I-1), (I-2) or (I-3) or intermediates used in the preparation or purification of the compounds of formula (I), (I-1), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.
Unless otherwise indicated, the structural formulae described herein and the compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds of the individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the invention are also within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
The compounds of the invention, as described herein, may independently be optionally substituted with one or more substituents, such as those of the general formula above, or as exemplified by the specific examples provided herein, subclasses, and classes of compounds encompassed by the invention. It will be appreciated that the term "independently optionally substituted with … …" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" denotes a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
When alkyl is a linking group, and "alkyl" is recited for this markush group definition, then "alkyl" represents a linked alkylene group.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Examples of alkylene groups include, but are not limited to: -CH 2 -、-CH 2 CH 2 -、-CH(CH 3 )CH 2 -, etc.
The term "alkylene-O-" means an alkylene group attached to the rest of the molecule through an oxygen atom, wherein the alkylene group has the definition as described herein.
The term "alkylene-NH-" means that the alkylene group is attached to the rest of the molecule via NH, wherein the alkylene group has the definition as described herein.
The term "oxo", i.e., =o, means that two hydrogens on the carbon atom are replaced with =o, i.e., -CH 2- Substituted with =o to give-C (=o) -.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl represents C 1-6 Hydroxyalkyl, i.e. C substituted by 1 or more hydroxy groups 1-6 Alkyl, preferably C 1-6 Hydroxyalkyl represents C substituted by 1 hydroxy 1-6 An alkyl group. At the position ofIn some embodiments, hydroxyalkyl represents C 1-4 A hydroxyalkyl group. In some embodiments, hydroxyalkyl represents C 1-3 A hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, OHCH 2 -、CH 2 OHCH 2 CH 2 CH 2 -、CH 2 OHCH 2 -、CH 2 OHCH 2 CHOHCH 2 -、CH(CH 3 )OHCH 2 CHOHCH 2 -, etc.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "alkoxyalkyl" refers to an alkyl group substituted with one alkoxy group, wherein the alkoxy and alkyl groups have the definitions as described herein. In some embodiments, alkoxyalkyl represents C 1-6 Alkoxy C 1-6 An alkyl group; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-4 An alkyl group; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-3 An alkyl group; in some embodiments, alkoxyalkyl represents C 1-3 Alkoxy C 1-3 An alkyl group. Examples of alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, and the like.
The term "halogen" means F (fluorine), cl (chlorine), br (bromine) or I (iodine).
The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms. In some embodiments, haloalkyl represents C 1-6 Haloalkyl, i.e. C 1-6 Alkyl substituted with 1 or more halogens. In some embodiments, haloalkyl represents C 1-4 A haloalkyl group. In some embodiments, haloalkyl represents C 1-3 A haloalkyl group. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl, 1-dibromoethyl, and the like.
The term "cycloalkyl" denotes a monovalent saturated monocyclic carbocyclic ring system. cycloalkyl-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, cycloalkyl contains 3 to 7 ring carbon atoms, i.e., C 3-7 Cycloalkyl groups. In one embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, i.e. C 3-6 Cycloalkyl; in another embodiment, cycloalkyl contains 3 to 5 carbon atoms, i.e. C 3-5 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. carbocycle-in-CH 2 Examples of groups that may be replaced by-C (=o) -include, but are not limited to: cyclopentanone, cyclobutanone, and the like. The cycloalkyl groups may independently be optionally substituted with one or more substituents described herein.
The term "cycloalkylene" refers to a divalent saturated monocyclic carbocyclic ring system. In cycloalkylene group-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, the cycloalkylene group contains 3-7 ring carbon atoms, i.e., C 3-7 Cycloalkylene radicals. In one embodiment, the cycloalkylene group contains 3 to 6 carbon atoms, i.e., C 3-6 A cycloalkylene group; in another embodiment, cycloalkyl contains 3 to 5 carbon atoms, i.e. C 3-5 Examples of cycloalkylene include, but are not limited to, 1-cyclopropylene, 1, 2-cyclopropylene, 1-cyclopentylene, 1-cyclohexylene, 1, 3-cyclopentylene, and the like. The cycloalkylene groups may be independently optionally substituted with one or more substituents described herein.
The term "monocyclic" means a saturated or unsaturated monocyclic carbocycle or a monocyclic heterocyclic ring system, wherein carbocycles and heterocyclic rings have the definitions as described herein. Wherein the monocyclic carbocyclic ring system is a carbon monocyclic ring and the monocyclic heterocyclic ring system is a heteromonocyclic ring.
The term "monocyclic group" means a monovalent saturated or unsaturated monocyclic carbocycle or monocyclic heterocyclic ring system, wherein carbocycle and heterocyclic ring have the definitions as described herein. In a monocyclic group-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, the monocyclic group contains 3-7 ring atoms, i.e., the monocyclic group is a 3-7 membered monocyclic group; in other embodiments, the monocyclic group contains 3-6 ring atoms, i.e., the monocyclic group is a 3-6 membered monocyclic group. Examples of monocyclic groups include, but are not limited to: cyclopropyl, cyclopentyl, cyclohexyl, 1, 2-cyclopentadienyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, furanyl, and the like. Preferably, the monocyclic group of the present invention is a monovalent saturated monocyclic carbocycle or monocyclic ringHeterocyclic ring systems. The monocyclic groups may independently be optionally substituted with one or more substituents described herein.
The term "monocyclic subunit" means a divalent saturated or unsaturated monocyclic carbocycle or monocyclic heterocycle system wherein carbocycles and heterocycles have the definitions as described herein. In a monocyclic subunit-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, the monocyclic subunit comprises 3 to 7 ring atoms, i.e., the monocyclic subunit is a 3 to 7 membered monocyclic subunit; in other embodiments, the monocyclic subunit contains 3-6 ring atoms, i.e., the monocyclic subunit is a 3-6 membered monocyclic subunit. Preferably, the monocyclic subunit of the present invention is a divalent saturated monocyclic carbocycle or a monocyclic heterocyclic ring system. Examples of monocyclic subunits include, but are not limited to: cyclopropylene, cyclopentylene, cyclohexylene, 1, 2-cyclopentadienyl, pyrrolidinylene, and the like. The monocyclic subunit may independently be optionally substituted with one or more substituents described herein.
The term "subunit" denotes a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein the heterocyclic ring has the definition as described herein. In the sub-mono-heterocyclic radical-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, the monoene group comprises 3-7 ring atoms, i.e., the monoene group is a 3-7 membered monoene group; in other embodiments, the monoene group comprises 3-6 ring atoms, i.e., the monoene group is a 3-6 membered monoene group. Preferably, the subunit heterocyclyl groups described herein are divalent saturated monocyclic heterocyclic ring systems.
The term "heterocycloalkylene" denotes a divalent saturated monocyclic heterocyclic ring system. In heterocycloalkylene group-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, the heterocycloalkylene group contains 3-7 ring atoms, i.e., the heterocycloalkylene group is a 3-7 membered heterocycloalkylene group; in other embodiments, the heterocycloalkylene group contains 3-6 ring atoms, i.e., the heterocycloalkylene group is a 3-6 membered heterocycloalkylene group. Examples of heterocycloalkylene groups include, but are not limited to: piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and the like.
The term'Heterocyclylalkyl "denotes an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl have the definitions as described herein. In some embodiments, the heterocyclylalkyl is a 3-12 membered heterocyclylc 1-6 An alkyl group; in other embodiments, the heterocyclylalkyl is a 3-6 membered heterocyclylc 1-6 An alkyl group; in some embodiments, the heterocyclylalkyl is a 3-6 membered heterocyclylc 1-4 An alkyl group. Examples of heterocyclylalkyl groups include, but are not limited to: pyrrolidinylmethyl, piperidinylmethyl, and the like.
The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein halogen and alkoxy have the definition as described herein. In some embodiments, haloalkoxy represents C 1-6 Haloalkoxy, i.e. C substituted by 1 or more halogens 1-6 An alkoxy group. In some embodiments, haloalkoxy represents C 1-4 Haloalkoxy groups. In some embodiments, haloalkoxy represents C 1-3 Haloalkoxy groups. Examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1, 2-difluoroethoxy, monochloroethoxy, and the like.
The term "alkanoyl" means an alkyl group attached to the remainder of the molecule through a carbonyl group, wherein alkyl has the definition as described herein, and carbonyl represents-C (=o) -. In some embodiments, the alkanoyl group represents C 1-6 An alkyl acyl group; in other embodiments, the alkanoyl group represents C 1-4 An alkyl acyl group. Examples of alkyl acyl groups include, but are not limited to: formyl, acetyl, and the like.
The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. Wherein cycloalkyl and alkyl have the definitions as described herein. In some embodiments, cycloalkylalkyl represents C 3-7 Cycloalkyl C 1-6 An alkyl group; in other embodiments, cycloalkylalkyl represents C 3-6 Cycloalkyl C 1-6 An alkyl group; in other embodiments, cycloalkylalkyl represents C 3-6 Cycloalkyl C 1-4 An alkyl group. Examples of cycloalkylalkyl groups include, but are not limited to: ring(s)Propylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.
The term "aryl" refers to a monovalent aromatic ring radical formed by the removal of a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl, and anthracene. When aryl is a linking group, and "aryl" is recited for this markush group definition, then "aryl" means a linked arylene group. The term "arylene" refers to a divalent aromatic ring radical formed by the removal of two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of aryl groups represented as linked arylene groups may include phenylene, naphthylene, and anthracenylene. The aryl groups may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" refers to a monovalent aromatic ring radical formed by the removal of a hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom composition heteroaryl or 5-10 membered heteroaryl contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" denotes a heteroaryl ring group or a 5 membered heteroaryl group containing 5 ring atoms, which contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-dithiotriazinyl, 1, 3-dithio, 3-triazolyl, 1, 3-triazolyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like. When heteroaryl is a linking group, and heteroaryl is recited for this markush group definition, then heteroaryl represents a linked heteroarylene group. The term "heteroarylene" refers to a divalent heteroaryl ring radical formed by removing two hydrogen atoms from a ring atom of a heteroaryl group. The heteroaryl groups may independently be optionally substituted with one or more substituents described herein.
The term "bridged cyclic group" means a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system having two or more non-adjacent ring atoms in common, including bridged carbocyclyl and bridged heterocyclyl. In some embodiments, the bridged ring radical is a 5-12 membered bridged ring radical. The bridged ring systems may be independently optionally substituted with one or more substituents described herein.
The term "acenylene" refers to a divalent non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system sharing two adjacent ring atoms, including an acenylene group and an acenylene group. In some embodiments, the acenylene is a 5-12 membered acenylene. The acenylene groups may independently be optionally substituted with one or more substituents described herein.
The term "spiroylene" means a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system formed by two rings sharing a single carbon atom, and includes spirocarbocyclic and spiroheterocyclic groups. In some embodiments, the spirosubunit is a 5-12 membered spirosubunit. The spirocyclic subunits may independently be optionally substituted with one or more substituents described herein.
The terms "carbocyclyl" and "carbocyclyl" are used interchangeably to refer to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having ring atoms that are both carbon atoms, including Shan Tanhuan groups, bridged carbocyclyl groups, and carbocyclyl groups and spiro carbocyclyl groups.
The terms "bridged carbocycle" and "bridged carbocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system having two or more non-adjacent ring carbon atoms in common, and the ring atoms are carbon atoms. Bridged carbocycle of-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, bridged carbocycles contain 6-12 ring carbon atoms, i.e., represent 6-12 membered bridged carbocycles; in other embodiments, bridged carbocycles contain from 6 to 10 ring carbon atoms, i.e., represent 6-10 membered bridged carbocycles. Examples of bridged carbocycles include, but are not limited to: bicyclo [3.1.1]Heptane, bicyclo [3.2.1]Octane, bicyclo [2.2.2]Octane, bicyclo [2.2.0]Hexane, octahydro-1H-indene, and the like. When bridged carbocycle or bridged carbocyclyl is a linking group, and bridged carbocycle or bridged carbocyclyl is recited for this markush group definition, then bridged carbocycle or bridged carbocyclyl represents a linked bridged carbocyclylene group. The term "bridged carbocyclyl" means a divalent bridged carbocyclyl group formed by removing two hydrogen atoms from a ring atom of a bridged carbocycle. The bridged carbocycle or bridged carbocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "spirocarbocyclyl" and "spirocarbocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring system formed by two carbocycles sharing one carbon atom. spiro-carbocycle-CH 2 The group may optionally be replaced by-C (=o) -. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, i.e., represents a 7-12 membered spirocarbocycle; in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, i.e., represents a 7-10 membered spirocarbocycle. Examples of spirocarbocycles include, but are not limited to: spiro [4.4 ]]Nonane, spiro [3.4 ]]Octane, spiro [4.5 ]]Decane, and the like. When a spiro carbocycle or spiro carbocyclyl is a linking group, and spiro carbocycle or spiro carbocyclyl is recited for this markush group definition, then spiro carbocycle or spiro carbocyclyl represents a linked spirocarbocyclylene group. The term "spiroylene" refers to a divalent spirocarbocyclic radical formed by removing two hydrogen atoms from the ring atoms of a spirocarbocyclic ring. The spirocarbocyclic ring or spirocarbonThe cyclic groups may independently be optionally substituted with one or more substituents described herein.
The terms "heterocycle" or "heterocyclyl" are used interchangeably and each represent a monovalent, non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or polycyclic ring system having 3 to 12 ring atoms, and containing at least 1 carbon atom, 1, 2 or 3 heteroatoms selected from O, N, S. Unless otherwise indicated, a heterocyclic group may be a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclyl contains 4-7 ring atoms, i.e., represents a 4-7 membered heterocyclyl; examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl, homopiperazinyl, homopiperidinyl, 1-dioxo-1, 3-thiomorpholin, and the like. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl. Examples of the nitrogen atom in the heterocyclic group being oxidized to an N-oxy compound include, but are not limited to, 1-dioxo-1, 3-thiomorpholine. When a heterocycle or heterocyclyl is the linking group and a heterocycle or heterocyclyl is recited for this markush definition, then the heterocycle or heterocyclyl represents the linked heterocyclylene. The term "heterocyclylene" refers to a divalent heterocyclic group formed by removal of two hydrogen atoms from a ring atom of a heterocycle. The heterocycle or heterocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "bridged heterocycle" or "bridged heterocyclyl" are used interchangeably and all representA non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system sharing two or more non-adjacent ring atoms and containing at least 1 carbon atom, 1, 2 or 3 heteroatoms selected from O, N, S. Bridged heterocyclic ring of-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, bridged heterocycles contain 6-12 ring atoms, i.e., represent 6-12 membered bridged heterocycles; in other embodiments, bridged heterocycles contain 6-10 ring atoms, i.e., represent 6-10 membered bridged heterocycles. Examples of bridged heterocycles include, but are not limited to: 3, 6-diazabicyclo [3.1.1 ]]Heptane, 3, 8-diazabicyclo [3.2.1 ]]Octane, 2-azabicyclo [2.2.1]Heptane, 6-azabicyclo [3.1.1 ]]Heptane, 3-azabicyclo [3.1.1 ]]Heptane, 8-azabicyclo [3.2.1 ]]Octane, 3-azabicyclo [3.2.1]Octane, 2-diazabicyclo [2.2.2]Octane, etc. When bridged heterocycle or bridged heterocyclyl is a linking group, and bridged heterocycle or bridged heterocyclyl is recited for this markush definition, then bridged heterocycle or bridged heterocyclyl represents a linked bridged heterocyclyl. The term "bridged heterocyclyl" means a divalent bridged heterocyclic group formed by removing two hydrogen atoms from a ring atom of a bridged heterocyclic ring. The bridged heterocycle or the bridged heterocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "spiroheterocycle" or "spiroheterocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated ring system formed by two rings sharing one carbon atom and containing 1, 2 or 3 heteroatoms selected from O, N, S. Spiro heterocyclic ring-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the spiroheterocycle contains 7-12 ring atoms, i.e., represents a 7-12 membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7-10 ring atoms, i.e., represents a 7-10 membered spiroheterocycle. Examples of spiroheterocycles include, but are not limited to: 4, 7-diazaspiro [2.5 ]]Octane, 2, 8-diazaspiro [4.5 ]]Decane, 2, 7-diazaspiro [4.5 ]]Decane, decane,2, 7-diazaspiro [3.5 ]]Decane, 2, 6-diazaspiro [3.3 ]]Heptane, 2, 7-diazaspiro [4.4 ]]Nonane, 3-azaspiro [5.5 ]]Undecane, 2, 7-diazaspiro [4.4 ]]Nonan-1-one, and the like. When a spiroheterocycle or spiroheterocyclyl is a linking group, and a spiroheterocycle or spiroheterocyclyl is recited for this markush group definition, then the spiroheterocycle or spiroheterocyclyl represents a linked spiroheterocyclyl subunit. The term "spiroylene" means a divalent spiroheterocyclic group formed by removing two hydrogen atoms from a ring atom of a spiroheterocyclic ring. The spiroheterocycle or spiroheterocyclyl may independently be optionally substituted with one or more substituents described herein.
The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In some embodiments, the term "aminoalkyl" refers to an alkyl group substituted with one amino group. In some embodiments, the term "aminoalkyl" means an amino C 1-6 An alkyl group. In other embodiments, the term "aminoalkyl" means an amino C 1-4 An alkyl group. In other embodiments, the term "aminoalkyl" means an amino C 1-3 An alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, amino-isopropyl, amino-isobutyl, amino-t-butyl, 1, 2-diaminoethyl, and the like.
The term "alkylamino" means an amino group substituted with one or two alkyl groups. In some embodiments, the term "alkylamino" denotes C 1-6 Alkylamino, i.e. representing a group consisting of one or two C' s 1-6 An alkyl-substituted amino group. In other embodiments, the term "alkylamino" denotes C 1-4 An alkylamino group. In other embodiments, the term "alkylamino" denotes C 1-3 An alkylamino group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, t-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, diisobutylamino, di-t-butylamino, and the like.
The term "alkylsulfonyl" denotes alkyl-S (=o) 2 -, i.e. alkyl through-S (=o) 2 -andthe remainder of the molecule is attached. In some embodiments, alkylsulfonyl represents C 1-6 An alkylsulfonyl group; in other embodiments, alkylsulfonyl represents C 1-4 An alkylsulfonyl group; in other embodiments, alkylsulfonyl represents C 1-4 An alkylsulfonyl group. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylmethylsulfonyl, n-propylmethylsulfonyl, isopropylmethylsulfonyl, n-butylmethylsulfonyl, and the like.
In the general formula (I) of the compounds of the invention, the left end of Q is connected to the ring a, the right end of Q is connected to M, for example, when Q is- (s=o) 2 NR 6 When in use, thenRepresentation->Likewise, the left end of ring A is connected to E and the right end of ring A is connected to Q.
In the general formula (I) of the compounds according to the invention, when T is alkylene-O-or alkylene-NH-,representation of
As described herein, unless otherwise specified, a ring substituent may be attached to the remainder of the molecule through any available position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.
If two attachment points are attached to the remainder of the molecule on a ring, as described herein, the two attachment points may be attached to the remainder of the molecule at any attachable location on the ring, with the ends of the attachment being interchangeable. For example, the sub-formula a1 of ring a represents that any two possible locations on the ring that may be connected may be used as points of connection (i.e., attachment points), while the two ends of the connection points may be interchanged. Preferably, if there are two attachment points on a ring that are attached to the remainder of the molecule, the two attachment points may be attached to the remainder of the molecule at any attachable position on the ring, and the two attachment points are attached to two different ring atoms on the ring.
Preferably, in the present invention, if one ring is a parallel ring or a spiro ring formed of two sub-rings, and two attachment points on the ring are respectively located on the two sub-rings, the two attachment points are respectively connected with the rest of the molecule at any connectable positions on the two sub-rings, and both ends of the connection may be interchanged. For example, the sub-formula a2 of ring a preferably represents that the two attachment points on the ring are linked to the rest of the molecule on the H1 ring and the H2 ring, respectively, while the two ends of the linkage may be interchanged; the substructures a3 of ring a preferably represent that the two attachment points on the ring are linked to the rest of the molecule on the H1 'ring and the H2' ring, respectively, while the two ends of the linkage may be interchanged.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethylA group, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: t W.Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al, prodrug: design and Clinical Applications, nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al, prodrugs of Phosphates and Phosphonates, journal of Medicinal Chemistry,2008,51,2328-2345.
"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxicAmmonium, quaternary ammonium salts and amine cations resistant to counter ion formation, e.g. halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 Sulfonate and aromatic sulfonate.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
"nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride.
The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "RET related cancer" as used herein refers to a cancer associated with or having a deregulation of the expression or activity or level of the RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any of them. Non-limiting examples of RET related cancers are described herein. The deregulation of the expression or activity or level of the RET gene, RET kinase or any one thereof is one or more point mutations in the RET gene.
The phrase "expression or activity or level of a RET gene, a RET kinase or any of them is deregulated" refers to a mutation in a gene (e.g., a translocation of a RET gene resulting in expression of a fusion protein, a deletion in a RET gene resulting in expression of a RET protein comprising at least one amino acid deletion compared to a wild-type RET protein, or a mutation in a RET gene resulting in expression of a RET protein having one or more point mutations, or an alternatively spliced form of RET mRNA of a RET protein resulting in deletion of at least one amino acid in a RET protein compared to a wild-type RET protein), or an amplification of a RET gene resulting in overexpression of a RET protein or an autocrine activity resulting from overexpression of a RET gene by a cell resulting in an increase in pathogenicity of activity of a kinase domain of a RET protein in a cell (e.g., constitutive activation of a kinase domain of a RET protein). As another example, the expression or activity or level imbalance of a RET gene, a RET kinase, or any of them may be a mutation in a RET gene encoding a RET protein having constitutive activity or having increased activity as compared to a protein encoded by a RET gene that does not include the mutation. For example, the disruption of expression or activity or level of the RET gene, RET kinase or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising a first RET portion comprising a functional kinase domain and a second portion of chaperone protein (i.e., not RET). In some examples, deregulation of RET genes, RET proteins, or expression or activity can be the result of gene translation of one RET gene with another RET gene.
Deregulation of expression or activity or levels of RET kinase, RET gene, or any (e.g., one or more) thereof, may contribute to tumorigenesis. For example, a RET kinase, a RET gene disorder, or a disorder of expression or activity or level of either of these may be a translocation, overexpression, activation, amplification, or mutation of the RET kinase, RET gene, or RET kinase domain. The translocation may include a translocation involving the RET kinase domain, the mutation may include a mutation involving the RET ligand binding site, and the amplification may be of the RET gene. Other disorders may include RET mRNA splice variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.
In some embodiments, the deregulation of the expression or activity or level of the RET gene, the RET kinase or any of them comprises one or more deletions (e.g., deletion of amino acid 4), insertions or point mutations in the RET kinase. In some embodiments, the deregulation of the expression or activity or level of a RET gene, a RET kinase or any one thereof comprises a deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.
The term "irritable bowel syndrome" includes diarrhea predominant, constipation predominant or alternating stool patterns, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, and the like.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H， 3 H， 11 C， 13 C， 14 C， 15 N， 17 O， 18 O， 18 F， 31 P， 32 P， 35 S， 36 Cl and Cl 125 I。
In another aspect, the compounds of the invention include isotopically enriched compounds defined in the invention, e.g., wherein a radioisotope, such as 3 H， 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 C. such isotopically enriched compounds are useful in metabolic studies (using 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiation therapy of a patient. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the one previously used unlabelled reagent.
In additionThe heavier isotopes are, in particular, deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is considered a substituent for a compound of formula (I), (I-1), (I-2), (I-3) or (I-4). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 、DMSO-d 6 Those solvates of (a).
Description of the Compounds of the invention
The invention provides a novel compound for inhibiting a transfection-phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutants and good inhibition selectivity on RET wild type and RET gene mutants.
In one aspect, the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
wherein R is 1 、X 1 、X 2 、X 3 、X 4 、X 5 、E、A、Q、M、T、Y、G、R a Q has the definition according to the invention.
In some embodiments, X 1 、X 2 、X 3 、X 4 And X 5 Each independently is CR 4 Or N.
In some embodiments, Y is O, NH or S.
In some embodiments, T is a bond, alkylene-O-alkylene, or alkylene-NH-, and the T is optionally selected from 1, 2, 3, or 4 of D, OH, F, cl, br, I, CN, NH 2 Substituted with alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, or alkylamino.
In some embodiments, ring G is a bridged carbocyclyl or bridged heterocyclyl.
In some embodiments, q is 0, 1, 2, 3, or 4.
In some embodiments, R a Is D, OH, NH 2 、F、Cl、Br、I、CN、NR 5 R 6 、OR 7 、-NR 6 C(＝O)R 7 、-S(＝O) 2 R 7 、-S(＝O)R 7 、-C(＝O)R 7 、-C(＝O)OR 7 Oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl.
In some embodiments, E is a bond, -NR 6 -or-O-.
In some embodiments, ring A is a bridged, fused or spiro-subunit, and ring A is optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and heterocyclylalkyl substituents.
In some embodiments, Q is a bond, - (CR) 2 R 3 ) t O-、-(CR 2 R 3 ) f -、-(CR 2 R 3 ) t -NR 6 -、-(C＝O)(CR 2 R 3 ) t -、-(C＝O)(CR 2 R 3 ) t -(S＝O) 2 (CR 2 R 3 ) f -、-(C＝O)(CR 2 R 3 ) t -NR 6 (CR 2 R 3 ) f -、-(C＝O)(CR 2 R 3 ) t -O(CR 2 R 3 ) f -、-(C＝O)NR 6 O(CR 2 R 3 ) f -、-(S＝O) 2 -NR 6 -(CR 2 R 3 ) t -、-(CR 2 R 3 ) f -(C＝O)-、-(CR 2 R 3 ) t -(C＝O)-NR 6 -(CR 2 R 3 ) t -、-(S＝O) 2 (CR 2 R 3 ) t -、-(CR 2 R 3 ) f -(S＝O) 2 (CR 2 R 3 ) t -、-(S＝O) 2 O-、-O(C＝O)-、-(C＝O)NR 6 -or-NR 6 (C＝O)-；
Each f is independently 1, 2, 3 or 4;
each t is independently 0, 1, 2, 3 or 4.
In some embodiments, M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally substituted with 1, 2, 3 or 4 groups selected from D, F, cl, CN, OH, NR 5 R 6 、OR 7 Substituted with alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl and cycloalkyl.
In some embodiments, R 1 H, D, CN, F, cl, br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, each R 2 And R is 3 OH, F, H, D, CN, cl, br, NH independently 2 Hydroxyalkyl, alkyl, alkylaminosA group, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;
or, R 2 、R 3 And the same carbon atom to which it is attached form a carbocyclic or heterocyclic ring;
in some embodiments, R 4 H, D, F, cl, br, alkyl or alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, R 5 Is H, D, alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein each of said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, NH 2 Substituted with alkyl amino, alkyl, alkylsulfonyl, alkoxy, aryl, and heteroaryl.
In some embodiments, R 6 Is H, D, alkyl or alkoxyalkyl, wherein each of said alkyl and alkoxyalkyl is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, R 7 Is OH, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In some embodiments, T is a bond, C 1-6 Alkylene, C 1-6 alkylene-O-, C 1-6 alkylene-O-C 1-6 Alkylene or C 1-6 alkylene-NH-and T is optionally selected from D, OH, F, cl, br, I, CN, C by 1, 2, 3 or 4 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-12 membered heteroaryl and C 1-6 The substituents of the alkylamino groups are substituted.
In some embodiments, T is a bond, -CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 2 -O-、-(CH 2 ) 2 -O-CH 2 -or- (CH) 2 ) 2 -NH-, and said T is optionally selected from the group consisting of 1, 2, 3 or 4 of D, OH, F, cl, br, I, CN, NH 2 、CF 3 、CHF 2 、CHCl 2 Substituted with methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino and dimethylamino.
In some embodiments, ring G is a 6-12 membered bridged carbocyclyl or a 6-12 membered bridged heterocyclyl.
In some embodiments, R a Is D, OH, NH 2 、F、Cl、Br、I、CN、NR 5 R 6 、OR 7 、-NR 6 C(＝O)R 7 、-S(＝O) 2 R 7 、-S(＝O)R 7 、-C(＝O)R 7 、-C(＝O)OR 7 Oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 1-6 A hydroxyalkyl group.
In some embodiments, R 5 H, D, C of a shape of H, D, C 1-6 Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, NH 2 、C 1-6 Alkylamino, C 1-6 Alkyl, C 1-6 Alkylsulfonyl, C 1-6 Alkoxy, C 6-10 Aryl and 5-10 membered heteroaryl.
In some embodiments, R 6 H, D, C of a shape of H, D, C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 1-6 Alkoxy C 1-6 Alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, R 7 Is OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl.
In some embodiments, ring G is of the following sub-structural formula:
wherein,
each Z is 1 Independently CH or N; and
Each Z is 2 Independently CH 2 C= O, NH, O, S, S = (O) or s= (O) 2 。
In some embodiments, ring G is of the following sub-structural formula:
in some embodiments, R a D, OH, F, CF of a shape of D, OH, F, CF 3 、CHCl 2 、CHF 2 、CH 2 F、CF 3 CH 2 、Cl、Br、I、CN、NH 2 、NHCH 3 、N(CH 3 ) 2 、--NHC(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O)CH 3 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OC(CH 3 ) 3 Oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl.
In some embodiments, R 5 H, D is methyl, ethyl, n-propyl, isopropyl, n-propylButyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, or pyrazolyl; wherein said methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl and pyrazolyl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, NH 2 Methyl, -S (=o) 2 CH 3 Substituents for methoxy, ethoxy and phenyl.
In some embodiments, R 6 Is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl are each independently and optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, R 7 Is OH, methyl, ethyl or NH 2 、N(CH 3 ) 2 Methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
In some embodiments, ring A is a 5-12 membered bridged ring, a 5-12 membered fused ring, or a 5-12 membered spiro ring, and ring A is optionally substituted with 1, 2, 3, or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments, ring a is of the following sub-structural formula:
wherein each Z 1a And Z 2a Independently CH 2 Or NH;
each Z is 3a And Z 7a Independently CH or N;
Z 4a o, S or NH;
each Z is 5a And Z 6a Independently CH 2 、O、S、S(＝O)、S(＝O) 2 C (=o) or NH;
each m and t is independently 0, 1 or 2;
each n and t1 is independently 0 or 1;
wherein each sub-structural formula of ring A is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments, ring a is of the following sub-structural formula:
wherein each sub-structural formula of ring A is independently optionally substituted with 1,2, 3 or 4 groups selected from F, cl, br, OH, oxo, NH 2 、NHCH 3 、CH 3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 Substituents selected from the group consisting of hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, M is H, D, a 5-10 membered heteroaryl, C 6-10 Aryl, C 3-7 Cycloalkyl or 3-12 membered heterocyclyl; and M is optionally selected from D, F, cl, CN, OH, NR by 1,2, 3 or 4 5 R 6 、OR 7 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 6-10 Aryl, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 1-6 Alkanoyl, 3-7 membered heterocyclyl and C 3-7 The substituents of cycloalkyl groups are substituted.
In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1 ]Heptyl, hexahydrofuro [3,4-c ]]Pyrrolyl, 3-azabicyclo [3.1.0]Hexalkyl octahydropyrrolo [1,2-a ]]Pyrazinyl or 5-azaspiro [2.4 ]]A heptyl group; and M is optionally selected from D, F, cl, CN, OH, CF by 1,2, 3 or 4 3 、CHCl 2 、CHF 2 、CH 2 F、CF 3 CH 2 、NH 2 、NHCH 3 、N(CH 3 ) 2 Substituted with a trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl group.
In some embodiments, M is phenyl, And M is optionally selected from D, F, cl, CN, OH, CF by 1,2, 3 or 4 3 、NH 2 、NHCH 3 、N(CH 3 ) 2 Trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranSubstituents for pyranyl, piperazinyl, cyclopropyl and cyclohexyl.
In some embodiments, M is
In some embodiments, R 1 H, D, CN, F, cl, br, methyl, ethyl or cyclopropyl, wherein said methyl, ethyl and cyclopropyl are independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, R 4 H, D, F, cl, br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups may independently optionally be substituted with 1, 2, 3 or 4 groups selected from F, cl, br, CN, NH 2 OH and NO 2 Is substituted by a substituent of (2).
In some embodiments, each R 2 And R is 3 OH, F, H, D, CN, cl, br, NH independently 2 、C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl;
or, R 2 、R 3 And the same carbon atom attached thereto may be a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
In some embodiments, each R 2 And R is 3 Independently OH, F, CF 3 、CHCl 2 、CHF 2 、H、D、CN、Cl、Br、NH 2 Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH) 3 ) 2 Methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridinyl or pyrazinyl;
Or, R 2 、R 3 And the same carbon atom to which it is attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
In some embodiments, Q is a bond, -O-, - (CH) 2 ) 2 O-、-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH(CH 3 )CH 2 NHCH 2 -、-(C＝O)OC(CH 3 ) 2 CH 2 -、-(C＝O)(CH 2 ) 2 (S＝O) 2 CH 2 -、-(C＝O)CH(OH)-、-(C＝O)CH(OH)CH 2 -、-(C＝O)-、-(S＝O) 2 -、-(C＝O)CH 2 CH(OH)-、-(C＝O)CH 2 -、-(C＝O)CH(CH 2 OH)-、-(C＝O)C(CH 3 ) 2 -、-(C＝O)CH 2 NHC(CH 3 ) 2 CH 2 -、-(C＝O)CH 2 CH(N(CH 3 ) 2 )-、-(C＝O)(CH 2 ) 2 N(CH 3 )CH 2 -、-(C＝O)C(CH 3 ) 2 CH 2 -、-(C＝O)C(OH)(CH 3 )CH 2 -、-(C＝O)CH 2 OCH 2 -、-(C＝O)(CH 2 ) 3 -、-(C＝O)CH(NH 2 )-、-(C＝O)(CH 2 ) 3 N(CH 3 )CH 2 -、-(C＝O)(CH 2 ) 2 -、-(C＝O)CH 2 CH(OH)CH 2 -、-(C＝O)CF 2 CH 2 -、-(C＝O)CH(OH)C(CH 3 ) 2 CH 2 -、-(C＝O)CH 2 C(CH 3 ) 2 CH 2 -、-(C＝O)CH 2 C(CH 3 )(OH)CH 2 -、-(S＝O) 2 CH 2 -、-(S＝O) 2 CH 2 C(CH 3 ) 2 CH 2 -、-(C＝O)CH(OCH 3 )-、-(C＝O)NHCH(CH 2 OH)(CH 2 ) 2 -、-(C＝O)NH-、-(C＝O)N(CH 3 )-、-(C＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-(C＝O)N(CH 2 CH 3 )(CH 2 ) 2 -、-(C＝O)NHC(CH 3 ) 2 CH 2 -、-(C＝O)N(CH 3 )(CH 2 ) 2 -、-(C＝O)NHCH 2 CH(CH 3 )CH 2 -、-(C＝O)NHCH 2 -、-(C＝O)NH(CH 2 ) 2 OCH 2 -、-(C＝O)N(CH 3 )(CH 2 ) 2 OCH 2 -、-(S＝O) 2 NHC(CH 3 ) 2 CH 2 -、-CH 2 CH(OH)C(CH 3 ) 2 CH 2 -、-CH(CH 3 )CH(OH)-、-CH 2 (C＝O)NHCH(CH 3 )CH 2 -、-CH 2 (C＝O)-、-(CH 2 ) 2 (C＝O)N(CH 3 )CH 2 -、-CH 2 CH(OH)-、-CH 2 CH(OH)CH 2 -、-CH 2 CH(OH)CH(CH 3 )CH 2 -、-(C＝O)CH(N(CH 3 ) 2 )-、-(C＝O)C(CH 3 ) 2 CH 2 OCH 2 -、-(C＝O)C(OCH 3 )(CF 3 )-、-(CH 2 ) 3 S(＝O) 2 CH(CH 3 )CH 2 -、-(C＝O)N(CH 2 CH 2 OCH 3 )CH 2 CH(OCH 3 )-、-CH 2 CH(OCF 3 )-、-CH 2 CH(OCH(CH 3 ) 2 )-、-CH 2 CH(OC(CH 3 ) 3 )-、-CH 2 CF 2 -、-CH(CH 3 )-、-CH 2 CH(OCH 3 )C(CH 3 ) 2 -、-CH 2 CH(N(CH 3 ) 2 )-、-NH-、-(C＝O)NHOCH 2 -、-(C＝O)NHOCH 2 (CHOH)-、-(S＝O) 2 (CH 2 CH 3 )-、-(S＝O) 2 O-、-(S＝O) 2 -NHC(CH 3 ) 2 -、-(CH 2 ) 2 (S＝O) 2 -、
In some embodiments, the compounds of the present invention have the structure of formula (IA), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (IA),
wherein R is 1 、X 1 、X 2 、X 3 、X 4 、X 5 、E、A、Q、M、T、G、R a Q has the definition according to the invention.
In some embodiments, the compounds of the present invention have the structure of formula (I-1), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-1),
wherein R is 1 、X 1 、X 2 、X 3 、X 4 、X 5 、E、Q、M、T、G、R a Q has the definition according to the invention;
ring A1 is of the sub-structural formula:
wherein each Z 1a And Z 2a Independently CH 2 Or NH;
and each sub-structural formula of ring A1 is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkylene and 3-6 membered heterocycloalkyleneIs substituted by a substituent of (2).
In some embodiments, ring A1 is of the formula:
wherein each sub-structural formula of ring A1 is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NH 2 、NHCH 3 、CH 3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 Substituents selected from the group consisting of hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, the compounds of the present invention have the structure of formula (IA 1), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (IA 1),
wherein R is 1 、X 1 、X 2 、X 3 、X 4 、X 5 、A、T、G、R a Q has the definition according to the invention;
wherein M is 1 Is heteroaryl, aryl.
In some embodiments, M 1 Is a 5-to 10-membered heteroaryl or C 6-10 An aryl group; and M is optionally selected from D, F, cl, CN, OH, NR by 1, 2, 3 or 4 5 R 6 、OR 7 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 6-10 Aryl, C 1-6 Alkoxy C 1-6 Alkyl, oxo, C 1-6 Alkanoyl, 3-7 membered heterocyclyl and C 3-7 The substituents of cycloalkyl groups are substituted.
In some embodiments, M 1 Is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl; pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl.
In some embodiments, M 1 Is that
In some embodiments, the compounds of the present invention have the structure of formula (I-1 aa), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-1 aa),
wherein R is 1 、X 1 、X 2 、X 3 、X 4 、X 5 、T、G、R a 、q、A1、M 1 With the definition according to the invention.
In some embodiments, the compounds of the present invention have the structure of formula (I-2) or (I-3), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-2) or (I-3),
wherein R is 1 、X 1 、X 2 、X 3 、X 4 、X 5 、E、Q、M、T、G、R a Q has the definition according to the invention;
each Z is 1 、Z 2 、Z 3a And Z 7a Independently CH or N;
each m and t is independently 0, 1 or 2;
each n and t1 is independently 0 or 1;
Each of which isIndependently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NR 5 R 6 、R 5 (C＝O)NR 6 -, a part of amino C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkylene are substituted.
In some embodiments of the present invention, in some embodiments,the following sub-structural formula is shown as follows:
the following sub-structural formula is shown as follows:
wherein the method comprises the steps ofIs independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, NH 2 、NHCH 3 、CH 3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, and cyclohexyleneThe substituents for hexyl and pyrrolidinyl are substituted.
In some embodiments, the compounds of the present invention have one of the following structures, or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,
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in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable adjuvant.
In another aspect, the invention also provides the use of the compound of the invention or the pharmaceutical composition of the invention in the preparation of a medicament for preventing or treating RET-related diseases.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of RET-related disorders.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a method of preventing or treating RET-related disorders comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I), (I-1), (IA 1), (I-1 aa), (I-2) or (I-3).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (I-1), (IA 1), (I-1 aa), (I-2) or (I-3).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
Also provided herein are methods of inhibiting cell proliferation in vitro or in vivo comprising contacting a cell with an effective amount of a compound of the invention or a pharmaceutical composition thereof.
Also provided herein are methods of treating Irritable Bowel Syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prophylactic or therapeutic treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention for the prophylaxis or treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.
In particular, salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological use, in relation to the other components that make up the formulation and the mammal being treated.
Salts of the compounds of the present invention also include salts of enantiomers isolated from intermediates used in the preparation or purification of the compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) or the compounds of formula (I), (I-1), (IA 1), (I-1 aa), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, for example, using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary, and cyclic ammonia such as piperidine, morpholine and piperazine, and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compounds of the present invention and pharmaceutical compositions, formulations and administration thereof
The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, e.g., RET mutants that are resistant to current standard of care treatment ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, resulting in reduced toxicity associated with inhibition of other kinases.
The pharmaceutical composition of the present invention comprises a compound represented by formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), a compound listed in the present invention, or a compound of the examples. The amount of the compound in the compositions of the invention is effective to treat or reduce RET-associated diseases or conditions in a patient, including RET-associated cancers, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which as used herein, include any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, in combination with the teachings of the present document, shows that various adjuvants can be used In the preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, pouch, paper or other container. If an excipient is used as a diluent, it may be a solid, semi-solid, or liquid material, which acts as a carrier, vehicle, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.
When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts thereof, may be administered as a raw chemical, and may also be provided as an active ingredient in a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including, but not limited to, a carrier, diluent or excipient, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit (e.g., cancer cytopenia). When separate active ingredients are used for separate administration, the term refers only to the ingredient. When applied in combination, the term refers to the combined amounts of the active ingredients that, when administered sequentially or simultaneously, result in a therapeutic effect. The compounds of the present invention, in particular the compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to a further aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises homogenizing a compound of the present invention, in particular a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for use in the intended use.
The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of the compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) admixed with a carrier material to prepare a single dosage form will vary depending upon the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound employed, the time of treatment and the age, sex, weight and condition of the patient. Preferred unit dosage forms are those containing daily or divided doses or suitable fractions thereof of the active ingredients described herein above. Treatment may be initiated with a small dose that is significantly less than the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimal effect is reached in this case. In general, the most desirable levels of concentration at which the compound is administered are those that generally provide effective results in terms of anti-tumor efficacy without causing any deleterious or toxic side effects.
Compositions comprising the compounds of the invention may be formulated in unit dosage forms, each dosage comprising from about 5 to about 1,000mg (1 g), more typically from about 100mg to about 500mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects or other patients, each unit containing a predetermined quantity of active material, i.e., a compound of formula I as provided herein, calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
In some embodiments, the compositions provided herein contain from about 5mg to about 50mg of the active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising from about 5mg to about 10mg, from about 10mg to about 15mg, from about 15mg to about 20mg, from about 20mg to about 25mg, from about 25mg to about 30mg, from about 30mg to about 35mg, from about 35mg to about 40mg, from about 40mg to about 45mg, or from about 45mg to about 50mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 50mg to about 500mg of the active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising from about 50mg to about 100mg, from about 100mg to about 150mg, from about 150mg to about 200mg, from about 200mg to about 250mg, from about 250mg to about 300mg, from about 350mg to about 400mg, or from about 450mg to about 500mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 500mg to about 1,000mg of the active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising from about 500mg to about 550mg, from about 550mg to about 600mg, from about 600mg to about 650mg, from about 650mg to about 700mg, from about 700 to about 750mg, from about 750mg to about 800mg, from about 800mg to about 850mg, from about 850mg to about 900mg, from about 900mg to about 950mg, or from about 950mg to about 1,000mg of an active ingredient.
The pharmaceutical composition is suitable for administration by any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or true subcutaneous injection or infusion) route. Such formulations may be prepared by any method known in the pharmaceutical arts, for example, by mixing the active ingredient with carriers or excipients. Oral administration or injection administration is preferred.
The invention also provides methods of treating an individual having RET-associated cancer comprising administering a compound of the invention before, during or after administration of another anti-cancer agent (e.g., not a compound of the invention).
The present invention provides a method for treating cancer in a patient in need thereof, the method comprising: (a) Determining whether the cancer in the patient is a RET related cancer (e.g., a RET related cancer including a RET related cancer having one or more RET inhibitor resistance mutations) (e.g., using regulatory agency approved, e.g., FDA approved, kits to identify a deregulation of the expression or activity or level of a RET gene, RET kinase, or any of them in the patient or in a biopsy sample of the patient, or by performing any non-limiting examples of assays described herein); and (b) administering to the patient a therapeutically effective amount of a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, if the cancer is determined to be a RET-associated cancer. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., another RET inhibitor, e.g., a RET inhibitor that is not a compound of the invention). In some embodiments, the subject is previously treated with a RET inhibitor that is not a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or is previously treated (e.g., after excision of a tumor or radiation therapy) with another anticancer agent.
In some embodiments of any of the methods described herein, a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), or (I-3) (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent selected from one or more other therapies or therapeutic (e.g., chemotherapeutic) agents.
Non-limiting examples of other therapeutic agents include: other RET targeted therapeutic agents (i.e., other RET kinase inhibitors: RET inhibitors other than the compounds of the invention), receptor tyrosine kinase targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obatacrax); cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutic agents, immune targeted agents and radiation therapy.
In some embodiments, the other RET targeted therapeutic agent is a multi-kinase inhibitor that exhibits RET inhibitory activity.
Non-limiting examples of RET targeted therapeutic agents include Alatinib, apatinib, cabatinib (XL-184), multi-vitamin tinib, lenvatinib, mo Taisha Ni, niladinib, ponatinib, lei Gela non-Ni, staitinib (sitovatinib) (MGCD 516), sunitinib, sorafenib, betaraninib, vandetanib, AUY-922 (5- (2, 4-dihydroxy-5-isopropyl-phenyl) -N-ethyl-4- [4- (morpholinomethyl) phenyl ] isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-2157, NVP-AST487 (1- [4- [ (4-ethylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] -3- [4- [6- (methylamino) pyrimidin-4-yl ] oxyphenyl ] urea), PZ-1, RPI-1 (1, 3-dihydro-5, 6-dimethoxy-3- [ (4-hydroxyphenyl) methylene ] -H-indol-2-one), RXDX-105 (1- (3- (6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) -3- (5- (1, 1-trifluoro-2-methylpropan-2-yl) isoxazol-3-yl) urea, SPP86 (1-isopropyl-3- (phenylethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine) and TG101209 (N- (1, 1-dimethylethyl) -3- [ [ 5-methyl-2- [ [4- (4-methyl-1-piperazinyl) phenyl ] amino ] -4-pyrimidinyl ] amino ] benzenesulfonamide).
Other therapeutic agents include RET inhibitors, such as those described, for example, in the following: U.S. patent No. 7,504,509;8,299,057;8,399,442;8,067,434;8,937,071;9,006,256; and 9,035,063; U.S. publication No. 2014/012339; 20160176865;2011/0053934;2011/0301157; 2010/034065; 2009/0227556; 2009/01330229; 2009/0099167;2005/0209195; international publication No. WO 2014/184069; WO 2014/072220; WO2012/053606; WO 2009/017838; WO 2008/031551; WO 2007/136103; WO 2007/087245; WO2007/057399; WO 2005/051366; WO 2005/062795; and WO2005/044835; and j.med.chem.2012,55 (10), 4872-4876, which is incorporated herein by reference in its entirety.
Also provided herein are methods of treating cancer comprising administering to a patient in need thereof a pharmaceutical combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and the amount of the other therapeutic agents are co-effective in treating cancer.
The compounds and compositions described herein may be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, the compounds or compositions of the present invention may be administered in combination with one or more compounds selected from the group consisting of: cabatinib (competriq), vandetanib (calfrest), sorafenib (NEXAVAR), sunitinib (SUTENT), lei Gela non-ni (stavanga), pranoptinib (iclucig), bevacizumab (avastin), crizotinib (XALKORI) or gefitinib (IRESSA). The compounds or compositions of the invention may be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the invention may be included with other therapeutic agents in a single formulation or in separate formulations.
In some embodiments, the compounds of the present invention may be used to treat Irritable Bowel Syndrome (IBS) in combination with one or more other therapeutic agents or therapies that are effective in the treatment of irritable bowel syndrome by acting through the same or different mechanisms of action. The at least one additional therapeutic agent may be administered with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as part of the same or separate dosage form, via the same or different route of administration, and according to the same or different administration schedule, according to standard pharmaceutical practice known to those skilled in the art. Non-limiting examples of other therapeutic agents for the treatment of Irritable Bowel Syndrome (IBS) include probiotics, fiber supplements (e.g. psyllium, methylcellulose), antidiarrheals (e.g. loperamide), bile acid binders (e.g. cholestyramine, colestipol, colesevelam), anticholinergic and anticonvulsants (e.g. hyoscyamine, dicyclomine), antidepressants (e.g. tricyclic antidepressants such as imipramine or nortriptyline or selective 5-hydroxytryptamine reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (e.g. rifaximin), alosetron and lubiprostone.
Use of the compounds and pharmaceutical compositions of the invention
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a RET related disease or disorder, wherein the RET related disease or disorder comprises RET related cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, e.g., RET mutants that are resistant to current standard of care treatment ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, resulting in reduced toxicity associated with inhibition of other kinases.
The invention provides application of the compound or the pharmaceutical composition thereof for inhibiting wild RET and RET mutants in preparation of medicines for preventing or treating diseases or symptoms related to the wild RET and RET mutants.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is a hematologic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchiolar lung cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gangliocytomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal carcinoma, appendicular carcinoma, astrocytoma, atypical teratoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, burkitt's lymphoma, carcinoid tumor, unknown primary cancer, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative tumor, colon cancer, colorectal cancer, craniopharyngeal tumor, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial carcinoma, ependymoma, esophageal carcinoma, sensory neuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell carcinoma, extrahepatic cholangiocarcinoma, ocular carcinoma, fallopian tube carcinoma, bone fibrocytoma, gallbladder carcinoma, gastric carcinoma, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell carcinoma, gestational trophoblastoma, glioma, hairy cell carcinoma, hairy cell leukemia, head and neck carcinoma, heart carcinoma, hepatocellular carcinoma, histiocytosis, hodgkin lymphoma, hypopharynx carcinoma, intraocular melanoma, islet cell carcinoma, pancreatic neuroendocrine carcinoma, kaposi's sarcoma, renal carcinoma, langerhans 'histiocytosis, laryngeal carcinoma, leukemia, lip and oral carcinoma, liver cancer, lung carcinoma, lymphoma, macroglobulinemia, bone malignant fibrous histiocytoma, bone carcinoma, melanoma, mecker's cell carcinoma, mesothelioma, metastatic squamous neck carcinoma, midline carcinoma, oral carcinoma, multiple endocrine tumor syndrome, multiple myeloma, mycosis, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, myelogenous leukemia, multiple myeloma, myeloproliferative neoplasms, nasal and sinus cancers, nasopharyngeal carcinoma, neuroblastoma, non-hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleural lung blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal carcinoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, szechurian syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, unknown primary carcinoma, urethral carcinoma, uterine sarcoma, vaginal carcinoma, vulval carcinoma and wilms' tumor.
In some embodiments, the RET related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, and cervical cancer. In some embodiments, the RET related cancer is RET fusion lung cancer or medullary thyroid cancer.
In some embodiments, the compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts and solvates thereof are useful in treating patients suffering from RET inhibitor resistance mutations that result in increased resistance to compounds or pharmaceutically acceptable salts or solvates that are not of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), e.g., substitutions at amino acid position 804, e.g., V804M, V L or V804E), by co-administration or as a subsequent treatment of existing drug therapies (e.g., other RET kinase inhibitors that are not compounds of formula (I), (IA 1), (I-1 aa), (I-2) or (I-3) or pharmaceutically acceptable salts or solvates thereof). Described herein are exemplary RET kinase inhibitors (e.g., other RET kinase inhibitors that are not compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), or (I-3), or pharmaceutically acceptable salts or solvates thereof). In some embodiments, the RET kinase inhibitor may be selected from the group consisting of cabotinib, vandetanib, alatinib, sorafenib, lenvatinib, plaitinib, multi-vitamin tinib, sunitinib, fortinib (foretinib), BLU667 and BLU6864.
In some embodiments of any of the methods or uses described herein, the Irritable Bowel Syndrome (IBS) comprises diarrhea predominant, constipation predominant, or alternating, functional abdominal distension, functional constipation, functional diarrhea, unspecific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.
The compounds and compositions according to the methods of the invention can be in any amount and by any route effective for treating or lessening the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compounds or compositions may be used in combination with one or more other therapeutic agents, as discussed herein.
General methods for the Synthesis of Compounds of the invention
In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3). The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Unless otherwise indicated, reagents were commercially available, e.g., reagents were purchased from commercial suppliers such as Ling Kai medicine, aldrich Chemical Company, inc., arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. The general reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin Chemie, inc., qingdao Tenglong chemical Co., ltd., and Qingdao ocean chemical works.
The anhydrous tetrahydrofuran is obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy with CDC1 3 Or DMSO-d 6 TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard for the solvent (reported in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, multiplet), m (multiplet ), br (broadside), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature kept at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Both spectrometers were equipped with a Agilent Zorbax SB-C18 column, 2.1X130 mm,5 μm format. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; the peak of the HPLC was read by recording the UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was a 0.1% acetonitrile formate solution (phase a) and a 0.1% ultrapure formate solution (phase B).
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X130 mm,4 μm,10 min, flow rate of 0.6mL/min,5-95% (0.1% aqueous formic acid in acetonitrile) and column temperature maintained at 40 ℃.
The following abbreviations are used throughout the present invention:
DMAC, DMA N, N-2-methylacetamide
PdCl 2 (dppf)CH 2 Cl 2 [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex
H 2 Hydrogen gas
Pd/C palladium carbon
NaOH sodium hydroxide
NH 4 Cl ammonium chloride
K 2 CO 3 Potassium carbonate
MeOH，CH 3 OH methanol
PE Petroleum ether
EA ethyl acetate
DCM dichloromethane
L liter (L)
mg
mL, mL mL
min
KI potassium iodide
DMF N, N-dimethylformamide
Ethyl acetate solution of HCl/EA hydrogen chloride
DMSO dimethyl sulfoxide
TLC thin layer chromatography
CH 3 CN acetonitrile
The following synthetic schemes describe the steps for preparing the disclosed compounds. Unless otherwise indicated, R 1 、X 1 、X 2 、X 3 、X 4 、X 5 、E、A、Q、M、T、R a Q has the definition according to the invention.
Synthesis scheme 1
Synthetic scheme for intermediate (IA-1 a):
intermediate compounds of formula (IA-1 a) may be obtained by reference to the synthetic steps of the above intermediate synthesis scheme. Wherein ring a is of the sub-structural formula:Hal 1 and Hal 2 Each independently F, cl, br, I, preferably Cl, br; pg (Pg) 1 Amino protecting groups such as Boc, etc.; pg (Pg) 2 Is a hydroxyl protecting group, such as benzyl, etc. Compounds of formula (IA-1 a-1) and compounds of formula (IA-1 a-2) are combined under suitable coupling agent conditions (e.g., palladium coupling agents, preferably PdCl 2 (dppf)CH 2 Cl 2 ) Coupling reaction in a suitable solvent (such as dioxane, etc.) to obtain a compound of formula (IA-1 a-3); compounds of formula (IA-1 a-3) and compounds of formula (IA-1 a-4) are suitable Under the conditions of a coupling agent (e.g., palladium coupling agent, preferably PdCl 2 (dppf)CH 2 Cl 2 ) Coupling reaction in a suitable solvent (such as toluene, etc.) to obtain a compound of formula (IA-1 a-5); reacting a compound of formula (IA-1 a-5) under suitable reaction conditions (e.g., in the presence of sodium hydroxide and hydrogen peroxide in a tetrahydrofuran solvent) to provide a compound of formula (IA-1 a-6); the compound of formula (IA-1 a-6) and the compound of formula (IA-1 a-7) undergo a coupling reaction to obtain the compound of formula (IA-1 a-8); reacting a compound of formula (IA-1 a-8) with a compound of formula (IA-1 a-9) under basic conditions to provide a compound of formula (IA-1 a-10); deamination of the compound of formula (IA-1 a-10) under acidic conditions affords a compound of formula (IA-1 a-11); reacting a compound of formula (IA-1 a-11) with a compound of formula (IA-1 a-12) under basic conditions to provide a compound of formula (IA-1 a-13); compounds of formula (IA-1 a-13) are useful in treating disorders such as H 2 Pd/C) to give the compound of formula (IA-1 a).
Intermediate (IA-3) synthesis scheme:
the intermediate (IA-3) can be prepared by the above-described synthetic schemes, wherein Hal and Hal 2 F, cl, br, I, cl and Br are preferred. Compounds of formula (IA-1 a-6) and compounds of formula (IA-2) are useful in treating disorders such as those wherein the base is K 2 CO 3 ) The reaction is then carried out in a suitable solvent such as N, N-dimethylformamide or DMSO to provide the compound of formula (IA-3).
Synthesis scheme 1:
the compounds of formula (IA) can be obtained by reference to the synthetic procedure of scheme 1. Wherein Hal is F, cl, br, I, preferably Cl and Br. The compound of formula (IA-1) and the compound of formula (IA-2) are mixed under proper conditions (such as alkaline conditions, the base is K) 2 CO 3 ) The reaction is then carried out in a suitable solvent such as N, N-dimethylacetamide or N, N-dimethylformamide to give the compound of formula (IA).
Synthesis scheme 2:
the compounds of formula (IAa) can be obtained by reference to the synthetic procedure of synthesis scheme 2. Compounds of formula (IA-3) and compounds of formula (IA-4) or salts of compounds of formula (IA-4) are useful in treating disorders such as those wherein the base is K 2 CO 3 ) Compound (IAa) is obtained in a suitable solvent (e.g. DMSO).
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Intermediate 1: 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Under room temperature, 6-bromo-4-methoxypyrazolo [1,5-a ] is added into a 1L single-mouth bottle in sequence]Pyridine-3-carbonitrile (50 g,198.36 mmol), water (16.5 mL, 912 mmol), sodium hydroxide (16.03 g,396.8 mmol), DMA (500 mL), stirring at room temperature for 5min, and slowly adding dodecyl mercaptan (97 mL,397 mmol) at 0deg.C, and after the addition, the reaction was transferred to 45℃overnight. The reaction solution was poured into 3L of ice water, saturated citric acid water was slowly added to adjust pH=5, stirred for half an hour, then allowed to stand, filtered, and the filter cake was washed with water and petroleum ether several times, and dried at 60℃to obtain 44.1g of a yellow solid as the objective product (yield 93.4%). Rf=0.35 (PE/ea=3:1); LC-MS: m/z=239.05 [ m+h ] ] + 。
Step 2: 3-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl triflate
To a 1L single flask was added 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (44.1 g,185 mmol), pyridine (45 mL,559 mmol), DCM (800 mL), and trifluoromethanesulfonic anhydride (50 mL,297.2 mmol) was slowly added at a temperature below-10℃and stirred for 1h before naturally warming to room temperature for reaction overnight. The DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL. Times.3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, dried over silica gel column chromatography (eluent PE/EA=50:1-25:1) to give 61.5g of the yellow-like solid as the target product in 89.7% yield. Rf=0.45 (PE/ea=5:1).
Step 3: 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
3-bromo-3-cyanopyrazolo [1,5-a ] is introduced into a 1L three-necked flask under nitrogen protection]Pyridin-4-yl trifluoromethanesulfonate (61.5 g,166 mmol), 2-fluoropyridine-5-boronic acid ester (44.5 g,200 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (6.8 g,8.3 mmol), 1, 4-dioxane (850 mL), was cooled to-10deg.C and potassium acetate solution (115 mL,345mmol,3 mol/L) was slowly added, and after stirring at this temperature for 1h, the reaction was allowed to spontaneously recover to room temperature and continue overnight. Filtering, washing filter cake by EA (500 mL multiplied by 3), washing an organic phase by water (500 mL), washing by saturated saline (250 mL), drying by anhydrous sodium sulfate, filtering, spinning the filtrate, purifying by silica gel column chromatography (eluent PE/DCM=2:1-0:1), collecting a target point, and spinning to obtain 49g of white solid which is the target product, wherein the yield is 93.0%. Rf=0.50 (PE/ea=1:1). LC-MS: m/z=318.10 [ m+h ] ] + 。 1 H NMR(400MHz,DMSO)δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H)。
Step 4:4- (6-Fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Under the protection of nitrogen in a 250mL single-port bottle, 6-bromo-4- (6-fluoropyridine-3-yl) pyrazolo [1,5-a ] is sequentially added]Pyridine-3-carbonitrile (8 g,25.23 mmol), pinacol diboronate (10 g,39.39 mmol), potassium acetate (10 g,101.9 mmol), redistilled toluene (150 mL), nitrogen sparged for another 10min and then added with [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (2.1 g,2.6 mmo), nitrogen was bubbled for 10min, and then the reaction was heated at 120℃overnight. Filtering with diatomite, washing (50 mL×3) filter cake with EA, washing (250 mL) with saturated salt water (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying, and collecting silicaColumn chromatography (eluent PE/dcm=2:1-0:1) and spin-drying was collected to give 8.5g of orange solid as the target product (yield 93.0%). Rf=0.15 (DCM). 1 H NMR(400MHz,CDCl 3 )δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H)。
Step 5:4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 250mL single vial was added successively 4- (6-fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (8.5 g,23 mmol), tetrahydrofuran (120 mL) was slowly added with sodium hydroxide solution (60 mL,120mmol,2 mol/L), hydrogen peroxide (14 mL,140mmol,30 mass%) under ice-bath conditions, and stirred at low temperature. After completion of the reaction, a sodium thiosulfate solution (50 mL,150mmol,3 mol/L) was slowly added, and after returning to room temperature, water (250 mL), EA was added for extraction (250 mL. Times.2), and the combined organic phases were washed with a 0.1M NaOH solution (500 mL. Times.2). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15min, and suction filtered to give a wet cake. The mother liquor was extracted with EA (250 ml×3), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and column chromatographed on silica gel (eluent DCM/meoh=100:0-100:1) to give a pale yellow solid. All solids were combined and dried at 50 ℃ to give 5.1g of the desired product as a pale yellow solid (86.0% yield). Rf=0.25 (DCM/meoh=100:1). LCMS: m/z=255.10 [ m+h ] ] + 。
Step 6:3- (5- (3-cyano-6-hydroxypyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-tert-butyl carboxylic acid
Into a 30mL microwave tube, 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] was sequentially added]Pyridine-3-carbonitrile (1.5 g,5.9 mmol), 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1]Heptane (2.3 g,12 mmol), N, N-diisopropylethylamine (2.0 mL,12 mmol), dimethyl sulfoxide (15 mL), sealed, and reacted at 80℃for 8h with microwaves. Diluting with water (50 mL), extracting with EA (100 mL. Times.5), washing with saturated organic phase saline (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate on silica gel column (eluent PE/EA=5:1-1; 1.5), and collecting the filtrate to obtain1.9g of yellow product was the desired product (yield 74.0%). Rf=0.5 (PE/ea=1:1.5). LC-MS: m/z=433.10 [ m+h ]] + 。
Step 7:3- (5- (6- (benzyloxy) -3-cyanopyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-tert-butyl-6-carboxylic acid ethyl ester
In a 25mL single vial was added 3- (5- (3-cyano-6-hydroxypyrazolo [1, 5-a) in sequence]Pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-t-butyl carboxylic acid (1 g,2.312 mmol), benzyl bromide (0.302 mL,2.54 mmol), potassium carbonate (0.9683 g,6.936 mmol), N, N-dimethylformamide (10 mL), and stirred overnight at 80 ℃. Saturated ammonium chloride (100 mL) was added at room temperature to quench, extracted with DCM (100 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin-dry silica gel chromatography (eluent PE/ea=5:1-2:1) to give 1.06g of the desired product as a yellow solid (yield 87.7%). Rf=0.7 (PE/ea=1:1). LC-MS: m/z=523.30 [ m+h ] ]。 1 H NMR(400MHz,CDCl 3 )δ8.37(s,1H),8.19(s,1H),8.17(d,J＝1.9Hz,1H),7.74(d,J＝8.7Hz,2H),7.42(dt,J＝11.9,7.4Hz,5H),7.18(d,J＝2.0Hz,1H),5.13(s,2H),4.31(d,J＝4.0Hz,2H),4.16(dd,J＝8.7,4.4Hz,2H),3.55(dd,J＝8.1,3.1Hz,2H),2.24–2.20(m,1H),2.01(d,J＝5.5Hz,1H),1.38(s,9H)。
Step 8:4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (benzyloxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
3- (5- (6- (benzyloxy) -3-cyanopyrazolo [1, 5-a)]Pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Ethyl heptane-3-tert-butyl-6-carboxylate (1.06 g,2.03 mmol), ethyl acetate hydrochloride solution (5 mL,20mmol,4 mol/L) and reacted overnight at room temperature. The reaction solution was spin-dried to give a yellow viscous material, which was dried at 60℃to give 1.0g of a yellow solid as the objective product (yield 100%). LC-MS: m/z=423.30 [ m-2hcl+h ]] + 。
Step 9: (6-methoxypyridin-3-yl) methanol
To a 25mL single-necked flask at 0deg.C was added 6-methoxy-3-pyridinecarbaldehyde (0.4 g,3 mmol), lithium aluminum hydride (0.06 g,2 mmol) and tetrahydrofuran (10 mL) in this order, and the reaction was carried out overnight at this temperature. EA (50 mL) was added,the reaction mixture was diluted with water (50 mL), extracted and separated, and then saturated NH 4 The organic layer was washed with Cl (50 mL) solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by silica gel chromatography (eluent DCM/ea=4:1) to give 0.38g of the desired product as a pale yellow liquid (yield 90.0%). LC-MS: m/z=140.15 [ m+h ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝1.8Hz,1H),7.62(dd,J＝8.5,2.4Hz,1H),6.75(d,J＝8.5Hz,1H),4.62(s,2H),3.93(s,3H)。
Step 10:5- (bromomethyl) -2-methoxypyridine
In a 25mL single-necked flask, (6-methoxypyridin-3-yl) methanol (0.38 g,2.7 mmol), methylene chloride (8 mL), phosphorus tribromide (0.31 mL,3.3 mmol) were sequentially added, and the mixture was reacted at 0℃for 30min. Dilute with DCM (25 mL), saturate K 2 CO 3 (25 mL) aqueous wash, the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning and taken directly to the next step without further purification.
Step 11:6- (benzyloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A25 mL single vial was charged with 4- (6- (3, 6-diazabicyclo [ 3.1.1) in sequence]Heptane-3-yl) pyridin-3-yl) -6- (benzyloxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (400 mg,0.8074 mmol), potassium carbonate (0.3382 g,2.423 mmol), N, N-dimethylformamide (8 mL), followed by slow addition of 5- (bromomethyl) -2-methoxypyridine (0.50 g,2.5 mmol) and stirring overnight at room temperature. The reaction mixture was diluted with water (25 mL), extracted with EA (50 ml×3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and purified by spin-drying on silica gel column (eluent DCM/meoh=1:0-20:1) to give 0.2889g of the desired product as a pale yellow solid (yield 65.82%). LC-MS: m/z=544.10 [ m+h ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.39(s,1H),8.22-8.17(m,2H),8.11(s,1H),8.02(s,1H),7.78(d,J＝8.8Hz,1H),7.42(dd,J＝14.9,7.1Hz,5H),7.19(s,1H),6.70(dd,J＝13.9,8.5Hz,2H),5.13(s,2H),3.92(s,3H),3.80(s,4H),3.59(s,4H),2.22(s,1H),2.01(s,1H)。
Step 12: 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
In a 50mL single vial was added sequentially 6- (benzyloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [ 3.1.1) ]Heptane-3-yl) pyridin-3-yl pyrazolo [1,5-a ]]Pyridine-3-carbonitrile (0.288 g,0.530 mmol), methanol (5 mL), palladium on carbon (0.03 g,10% mass), and hydrogen were replaced several times and stirred overnight at room temperature. The reaction solution is filtered, the filter cake is washed by methanol, and the filtrate is dried by spin to obtain 240mg of light yellow solid which is the target product (yield 100.0%). LC-MS: m/z=454.30 [ m+h ]]。 1 H NMR(400MHz,CDCl 3 )δ8.39(d,J＝1.7Hz,1H),8.28(d,J＝2.0Hz,1H),8.21(s,1H),8.17-8.12(m,1H),7.81(dd,J＝8.1,2.2Hz,2H),7.14(s,1H),6.78(d,J＝8.6Hz,1H),6.70(d,J＝8.3Hz,1H),5.37(s,1H),4.00-3.90(m,5H),3.73(s,4H),3.51(s,2H),2.27-2.21(m,1H),2.03(d,J＝6.6Hz,1H)。
Intermediate 2:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
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Step 1: (1S, 4S) -5- (2-chloroethyl) -2-oxa-5-azabicyclo [2.2.1] heptane
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] at 0 DEG C]Heptane hydrochloride (1.00 g,7.38 mmol) in acetone (15 mL) was added K 2 CO 3 (3.06 g,22.1 mmol) and KI (1.84 g,11.1 mmol), and after stirring for 15min, 1-bromo-2-chloroethane (1.59 g,11.1 mmol) was slowly added, and the mixture was allowed to warm to room temperature and stirred for 4h. TLC monitoring of the reaction (DCM/CH after PE/EA (v/v=2/1)) 3 OH (v/v=20/1), rf=0.31), and the starting material reacted completely. Slowly adding water for quenching reaction, extracting with EA (10 mL×3), washing organic phase with water, drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography, and eluting with DCM/CH 3 OH (v/v=40/1-20/1) to obtain colorless viscous liquid 0.49g as target product with 41% yield. 1 H NMR(400MHz,CDCl 3 )δ4.41(s,1H),4.01(d,J＝7.9Hz,1H),3.70–3.61(m,1H),3.56(s,1H),3.53(d,J＝6.9Hz,2H),3.06–2.94(m,2H),2.94–2.88(m,1H),2.58(d,J＝9.9Hz,1H),1.87(d,J＝9.8Hz,1H),1.76(d,J＝9.8Hz,1H).。
Step 2:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ]]Pyridine-3-carbonitrile (20 mg,0.08mmol, intermediate 4) and (1S, 4S) -5- (2-chloroethyl) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane (20 mg,0.12 mmol) was dissolved in DMF (6 mL) and K was slowly added 2 CO 3 (22 mg,0.16 mmol) and stirred for 10min. After that, the temperature was raised to 50℃and the reaction was continued for 12 hours. TLC monitoring of the reaction (DCM/CH after PE/EA (v/v=2/1)) 3 OH (v/v=10/1), rf=0.07), and the starting material reacted completely. The reaction was stopped, the reaction mixture was cooled to room temperature, extracted with EA (20 mL. Times.3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography, eluent DCM/CH 3 OH (v/v) =50/1-20/1 to obtain 12mg of yellowish-brown solid as the target product with 40% yield. LC-MS: m/z=380.3 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.41(d,J＝3.4Hz,1H),8.28(s,1H),8.24(s,1H),8.08–7.98(m,1H),7.21(d,J＝1.9Hz,1H),7.18–7.11(m,1H),4.51(s,1H),4.30(brs,2H),4.22–4.16(m,1H),3.93–3.80(m,1H),3.76(d,J＝8.2Hz,1H),3.36–3.26(m,1H),3.25(brs,2H),2.83(d,J＝8.8Hz,1H),1.91(d,J＝9.5Hz,2H)。
Intermediate 3:4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 3-azabicyclo [3.2.1] octan-8-one hydrochloride
Into a 25mL single vial was added 8-oxo-3-azabicyclo [3.2.1]Tert-butyl octane-3-carboxylate (1.0 g,4.4 mmol) was dissolved by adding EA (5 mL) at room temperature, HCl/EA (6 mL,24mmol,4 mol/L) was added and stirred at room temperature for 1h. After the reaction is finished, the reaction solution is directly concentrated to obtain 700mg of white solid which is the product, and the yield is 98.00%. LC-MS: m/z=126. 25[M+H] + 。
Step 2:3- (2-chloroethyl) -3-azabicyclo [3.2.1] octan-8-one
25mL double-necked flask was charged with 3-azabicyclo [3.2.1]Octane-8-one hydrochloride (300 mg,1.86 mmol), potassium carbonate (1.1 g,7.6 mmol), acetonitrile (5 mL), 1-bromo-2-chloroethane (0.5 mL,6 mmol), and after the addition was completed, the reaction was performed at room temperature for 15h. After the reaction, insoluble matters are removed by suction filtration, the filtrate is directly concentrated and subjected to silica gel column chromatography, and the eluent is DCM/MeOH (v/v) =20/1, so that 90mg of colorless liquid is obtained as a product, and the yield is 25.84%. LC-MS: m/z=188.20 [ m+h ]] + 。
Step 3:4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A25 mL single vial was charged with 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] sequentially]Pyridine-3-carbonitrile (110 mg,0.4327mmol, intermediate 4), potassium carbonate (178 mg,1.2879 mmol), 3- (2-chloroethyl) -3-azabicyclo [ 3.2.1)]Octan-8-one (910 mg,4.8489 mmol) was dissolved in DMSO (2 mL) and reacted at 80℃for 2h. After the reaction was stopped, 10mL of water was added to the reaction mixture, ea (40 ml×2) was extracted, the organic phase was washed with water (10 ml×4), saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was chromatographed on a silica gel column with DCM/MeOH (v/v=10/1) as eluent to give 70mg of a yellow solid as a product in 39.90% yield. LC-MS: m/z=406.15 [ m+h ] ] + ； 1 H NMR：(400MHz,CDCl 3 )δ8.40(s,1H),8.27(d,J＝2.0Hz,1H),8.23(s,1H),8.02(dd,J＝11.5,4.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.13(dd,J＝8.5,2.7Hz,1H),4.24(t,J＝5.6Hz,2H),3.65(s,2H),3.09(t,J＝5.6Hz,2H),2.71(d,J＝12.6Hz,2H),2.25(d,J＝15.6Hz,2H),2.08(s,2H),1.67(d,J＝8.0Hz,2H)。
Intermediate 4:4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Room temperature conditionsSequentially adding 6-bromo-4-methoxy pyrazolo [1,5-a ] into a 1L single-mouth bottle]Pyridine-3-carbonitrile (50 g,198.36 mmol), water (16.5 mL, 912 mmol), sodium hydroxide (16.03 g,396.8 mmol), DMAC (500 mL), stirring at room temperature for 5min, and slowly adding dodecanethiol (97 mL,397 mmol) at 0deg.C, and after the addition, the reaction was transferred to 45℃overnight. The reaction solution was poured into 3L of ice water, and saturated aqueous citric acid solution was slowly added to adjust ph=5, stirred for half an hour, then allowed to stand, filtered, and the filter cake was washed with water and petroleum ether several times, and dried at 60 ℃ to obtain 44.1g of a yellow solid as the target product (yield 93.4%). Rf=0.35 (PE/EA (v/v=3/1). LC-MS: m/z=239.05 [ m+h)] + 。
Step 2: 6-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl triflate
To a 1L single flask was added 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (44.1 g,185 mmol), pyridine (45 mL,559 mmol), DCM (800 mL), and trifluoromethanesulfonic anhydride (50 mL,297.2 mmol) was slowly added at a temperature below-10℃and stirred for 1h before naturally warming to room temperature for reaction overnight. The DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL. Times.3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, followed by purification by silica gel column chromatography (eluent: PE/EA (v/v=50/1-25/1)) to give 61.5g of the title product as a yellow-like solid in 89.7% yield. Rf=0.45 (PE/EA (v/v=5/1).
Step 3: 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Under the protection of nitrogen, 6-bromo-3-cyano pyrazolo [1,5-a ] is added into a 1L three-mouth bottle]Pyridin-4-yl trifluoromethanesulfonate (61.5 g,166 mmol), 2-fluoropyridine-5-boronic acid ester (44.5 g,200 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (6.8 g,8.3 mmol), 1, 4-dioxane (850 mL), was cooled to-10deg.C and potassium acetate solution (115 mL,345mmol,3 mol/L) was slowly added, and after stirring at this temperature for 1h, the reaction was allowed to spontaneously recover to room temperature and continue overnight. Filtering, washing the filter cake with EA (500 mL. Times.3), washing the filtrate with water (500 mL), washing the filtrate with saturated saline (250 mL), drying over anhydrous sodium sulfate, filtering, spin-drying the filtrate, and purifying by silica gel column chromatography (eluent: PE/DCM (v/v=2/1-0/1), to obtain 49g of white solidThe product is the target product, and the yield is 93.0%. Rf=0.50 (PE/EA (v/v=1/1)). LC-MS: m/z=318.10 [ m+h ]] + ； 1 H NMR(400MHz,DMSO)δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H)。
Step 4:4- (6-Fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Under the protection of nitrogen in a 250mL single-port bottle, 6-bromo-4- (6-fluoropyridine-3-yl) pyrazolo [1,5-a ] is sequentially added]Pyridine-3-carbonitrile (8 g,25.23 mmol), pinacol diboronate (10 g,39.39 mmol), potassium acetate (10 g,101.9 mmol), redistilled toluene (150 mL), nitrogen sparged for another 10min and then added with [1,1' -bis (diphenylphosphine) ferrocene ]Palladium dichloride dichloromethane complex (2.1 g,2.6 mmo), nitrogen was bubbled for 10min, and then the reaction was heated at 120℃overnight. Diatomaceous earth filtration, EA washing (50 mL. Times.3) of the filter cake, organic phase washing (250 mL), saturated brine (250 mL), drying over anhydrous sodium sulfate, filtration, spin-drying, silica gel column chromatography (eluent PE/DCM (v/v=2/1-0/1), and collection of spin-drying gave 8.5g of an orange solid as the target product (yield 93.0%). Rf=0.15 (DCM). 1 H NMR(400MHz,CDCl 3 )δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H)。
Step 5:4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 250mL single vial was added successively 4- (6-fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (8.5 g,23 mmol), tetrahydrofuran (120 mL) was slowly added with sodium hydroxide solution (60 mL,120mmol,2 mol/L), hydrogen peroxide (14 mL,140mmol,30 mass%) under ice-bath conditions, and stirred at low temperature. After completion of the TLC monitoring, a sodium thiosulfate solution (50 mL,150mmol,3 mol/L) was slowly added, and after returning to room temperature, water (250 mL), EA extraction (250 mL. Times.2) was performed, and the combined organic phases were washed with a 0.1M NaOH solution (500 mL. Times.2). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15min, and suction filtered to give a wet cake. Mother liquor EA extraction (250 mL x 3), Combining all organic phases, drying over anhydrous sodium sulfate, filtering, spin-drying, column chromatography on silica gel (eluent DCM/MeOH (v/v=100/0-100/1) to give pale yellow solid. Combining all solids, oven drying at 50deg.C to give 5.1g of pale yellow solid as the target product (yield 86.0%). Rf=0.25 (DCM/MeOH=100:1). LC-MS: m/z=255.10 [ M+H)] + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H),8.42-8.40(m,1H),8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H)。
Example 1:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: (1S, 4S) -5- (2-chloroethyl) -2-oxa-5-azabicyclo [2.2.1] heptane
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] in sequence in a 50mL single-necked flask]Heptane hydrochloride (300 mg,2.2126 mmol), potassium carbonate (1.26 g,9.11 mmol), acetone (4.5 mL), stirring for 5min under ice bath conditions, and then 1-bromo-2-chloro-ethane (0.3 mL,4 mmol) was added dropwise, and the reaction was allowed to warm to room temperature overnight. The reaction solution was filtered, the filter cake was washed with an appropriate amount of EA, the mother liquor was dried by spin-drying, and silica gel column chromatography (eluent PE/ea=7/1-4/1) was collected to obtain 102mg of a colorless oily liquid, which was the target product (yield: 28.52%). 1 H-NMR(400MHz,CDCl 3 ):δ4.40(s,1H),4.00(d,J＝7.9Hz,1H),3.63(dd,J＝7.9,1.6Hz,1H),3.56-3.48(m,3H),3.02-2.84(m,3H),2.56(d,J＝9.9Hz,1H),1.85(dd,J＝9.8,1.6Hz,1H),1.77-1.72(m,1H)。
Step 2:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo) is sequentially added to a 10mL single-necked flask[3.1.1]Heptane-3-yl) pyridin-3-yl pyrazolo [1,5-a ]]Pyridine-3-carbonitrile (20 mg,0.04410mmol, see intermediate 1 Synthesis of), (1S, 4S) -5- (2-chloroethyl) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane (22 mg,0.13611 mmol), potassium carbonate (0.025 g,0.18 mmol), DMA (1.5 mL), oil bath stirring overnight at 80 ℃. After TLC showed completion of the reaction, the reaction mixture was poured into ice water (10 mL), EA extracted (30 ml×3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the mother liquor was spin-dried on silica gel column chromatography (DCM/meoh=50/1-10/1) to give 11.3mg of an off-white solid as the target product (yield 44.2%). LC-MS (ES-API) m/z=579.1 [ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.39(d,J＝2.2Hz,1H),8.21(s,1H),8.15(d,J＝1.9Hz,1H),8.10(d,J＝1.7Hz,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.65(dd,J＝8.5Hz,1H),7.13(d,J＝2.0Hz,1H),6.70(dd,J＝12.7,8.7Hz,2H),4.43(s,1H),4.17-4.11(m,2H),4.09(d,J＝8.0Hz,1H),3.92(s,3H),3.88-3.82(m,2H),3.82-3.78(m,2H),3.68(d,J＝8.0Hz,1H),3.63-3.58(m,4H),3.16-3.05(m,3H),2.75-2.69(m,1H),2.70-2.65(m,1H),2.05-2.00(m,1H),1.93-1.90(m,1H),1.81-1.78(m,1H),1.68-1.64(m,1H)。HPLC:89.75％。
Example 2:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (4-Methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Into a 25mL single-necked flask was added hexahydropyrrolo [3,4-c ]]Pyrrole-2 (1H) -5-carboxylic acid tert-butyl ester (1.0 g,4.7 mmol), 4-methoxybenzoic acid (1.1 g,7.2 mmol) was dissolved in DCM, after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.8 g,9.4 mmol) and 4-dimethylaminopyridine (1.2 g,9.8 mmol) were added and reacted at room temperature for 20H. After stopping the reaction, 10mL of water was added to the reaction mixture, the mixture was extracted with DCM (30 mL) in the aqueous phase, the organic phases were combined and washed with water (10 mL. Times.2), and anhydrous sodium sulfate was added After drying, concentration and column chromatography on silica gel eluting with DCM-DCM/MeOH (v/v=50/1) gave 1.3g as colorless liquid as product in 81.25% yield. LC-MS: m/z=291.20 [ M-tBu+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.51(d,J＝8.7Hz,2H),6.95(d,J＝8.7Hz,2H),3.79(s,3H),3.68(s,2H),3.56–3.33(m,4H),3.20(s,1H),3.05(s,1H),2.85(s,2H),1.39(s,9H)。
Step 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (4-methoxyphenyl) methanone dihydrochloride
A25 mL single vial was charged with 5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (600 mg,1.732 mmol) was dissolved by adding EA (5 mL), HCl/EA (4 mL,16mmol,4 mol/L) was added and reacted at room temperature for 1H after the addition was completed. After TLC detection reaction is finished, the reaction liquid is directly concentrated, and 470mg of solid is obtained after drying, and the yield is 95.95%. LC-MS: m/z=247.25 [ m+h ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.50(d,J＝8.7Hz,2H),6.96(d,J＝8.7Hz,2H),3.78(s,3H),3.66(s,2H),3.54(d,J＝3.1Hz,1H),3.52(d,J＝2.6Hz,1H),3.32(s,2H),2.99(s,4H)。
Step 3:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 10mL single vial was added 6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (26 mg,0.06853mmol, intermediate 2), hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) (4-methoxyphenyl) methanone dihydrochloride (30 mg,0.1061 mmol), potassium carbonate (55 mg,0.39795 mmol), DMSO (1.5 mL) and oil bath at 90℃for 14H. After the reaction solution was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, and filtered, the filtrate was concentrated under reduced pressure to give silica gel column chromatography with eluent DCM/MeOH (v/v=50/1-10/1), and 20mg of a yellow solid was obtained as a product, yield: 48.18%. LC-MS: m/z=606.30 [ m+h ] ] + ； 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝2.2Hz,1H),8.20(s,1H),8.14(d,J＝2.0Hz,1H),7.70(dd,J＝8.7,2.4Hz,1H),7.52(d,J＝8.7Hz,2H),7.10(d,J＝2.0Hz,1H),6.91(d,J＝8.7Hz,2H),6.50(d,J＝8.8Hz,1H),4.44(s,1H),4.16–4.10(m,2H),4.09(d,J＝8.0Hz,1H),4.02(s,1H),3.84(s,4H),3.77–3.72(m,1H),3.69(dd,2H),3.61(s,1H),3.51(s,3H),3.17–3.02(m,5H),2.67(d,J＝9.9Hz,1H),2.62(s,1H),1.92(d,J＝9.8Hz,1H),1.80(d,J＝9.9Hz,1H)。
Example 3:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2, 3-Dibenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Into a 25mL single vial was added hexahydro-pyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (500 mg,2.36 mmol), 2, 3-dimethylbenzoic acid (530 mg,3.5 mmol), was dissolved by the addition of DCM, after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (903 mg,4.71 mmol) and 4-dimethylaminopyridine (580 mg,4.75 mmol) were added and reacted at room temperature for 17H. 10mL of water was added to the reaction solution, the aqueous phase was extracted with DCM (30 mL), the organic phases were combined and washed with water (10 mL. Times.2), dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column with PE-PE/EA (v/v=1/1) as eluent to give 660mg of colorless viscous liquid as the product in a yield of 81.37%. LC-MS: m/z=289.25 [ m-tbu+h ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.18(d,J＝7.3Hz,1H),7.12(t,J＝7.5Hz,1H),7.01(d,J＝7.3Hz,1H),3.69(dd,J＝12.3,7.7Hz,1H),3.50(s,1H),3.44–3.36(m,2H),3.31–3.24(m,1H),3.17(dd,J＝11.2,4.8Hz,1H),3.03(dd,J＝11.2,4.5Hz,1H),2.95–2.76(m,3H),2.25(s,3H),2.10(s,3H),1.39(s,9H)。
Step 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2, 3-dimethylphenyl) methanone dihydrochloride
A25 mL single vial was charged with 5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester Butyl ester (330 mg,0.96 mmol) was dissolved by adding EA (3 mL), HCl/EA (2 mL,8mmol,4 mol/L) was added, and the mixture was reacted at room temperature for 1h after the completion of the addition. White solid is separated out in the reaction process, after TLC detection of the raw materials is finished, the reaction liquid is directly concentrated to obtain white solid, and the white solid is dried at 60 ℃ in a vacuum drying oven to obtain 260mg of the product, and the yield is 85.54%. LC-MS: m/z=245.30 [ m+h ]] + ； 1 H NMR(400MHz,DMSO)δ7.18(d,J＝7.3Hz,1H),7.13(t,J＝7.5Hz,1H),7.03(d,J＝7.3Hz,1H),3.73(dd,J＝12.6,7.9Hz,1H),3.54(dd,J＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11–2.99(m,3H),3.00–2.86(m,2H),2.25(s,3H),2.12(s,3H)。
Step 3:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 10mL single vial was added 6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (26 mg,0.07mmol, intermediate 2), (hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) (2, 3-dimethylphenyl) methanone dihydrochloride (30 mg,0.11 mmol), potassium carbonate (55 mg,0.40 mmol), DMSO (1.5 mL) and oil bath at 90℃for 13H. After cooling the reaction to room temperature, 5mL of water, EA (20 mL. Times.2) was added to extract, the organic phase was washed with water (5 mL. Times.3), saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, and filtered, the filtrate was concentrated under reduced pressure on a silica gel column, and the eluent was DCM/MeOH (v/v=50/1-20/1), to give 20mg of a yellow solid as a product in 48.34% yield. LC-MS: m/z=604.30 [ m+h ] ] + ； 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝2.0Hz,1H),8.19(s,1H),8.15(d,J＝1.8Hz,1H),7.70(dd,J＝8.7,2.3Hz,1H),7.18–7.09(m,3H),7.05(d,J＝7.0Hz,1H),6.49(d,J＝8.7Hz,1H),4.44(s,1H),4.16–4.08(m,3H),4.00(dd,J＝12.7,7.7Hz,1H),3.87(dd,J＝10.5,7.8Hz,1H),3.79–3.70(m,2H),3.68(d,J＝8.0Hz,1H),3.61(s,1H),3.54–3.46(m,2H),3.40(dd,J＝10.8,4.1Hz,1H),3.18–3.02(m,6H),2.67(d,J＝10.1Hz,1H),2.28(s,3H),2.21(s,3H),1.92(d,J＝10.0Hz,1H),1.79(d,J＝9.7Hz,1H)。
Example 4:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:6- (4-Methoxybenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
2, 6-diazaspiro [3.3] was added to a 50mL single vial]Heptane-2-carboxylic acid tert-butyl ester (500 mg,2.52 mmol), 4-methoxybenzoic acid (576 mg,3.79 mmol), DCM was added followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (480 mg,5.11 mmol), 4-dimethylaminopyridine (636 mg,5.21 mmol) and the reaction was carried out at room temperature for 18h. To the reaction was added 5mL of water, the aqueous phase was extracted with DCM (20 mL), the organic phases were combined, washed with water (5 ml×2), dried over anhydrous sodium sulfate, and chromatographed on silica gel with DCM-DCM/MeOH (v/v=50/1) as eluent to give 270mg of a white solid as the product in 32.21% yield. LC-MS: m/z=333.20 [ m+h ]] + ；
1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),4.35(d,J＝28.9Hz,4H),4.10(s,4H),3.84(s,3H),1.44(s,9H)。
Step 2: (4-methoxyphenyl) (2, 6-diazaspiro [3.3] heptan-2-yl) methanone
Into a 25mL single vial was added 6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (200 mg,0.62 mmol) was dissolved by adding DCM (2 mL), trifluoroacetic acid (0.9 mL,10 mmol) was added at 0deg.C, and the reaction was carried out at room temperature for 6h after the addition was completed. The reaction solution was directly concentrated to obtain 130mg of colorless liquid as a product, and the yield was 93.01%. LC-MS: m/z=233.20 [ m+h ] ] + 。
Step 3:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 10mL single vial was added 6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [ 1S)2.2.1]Heptane-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (22 mg,0.058mmol, intermediate 2), (4-methoxyphenyl) (2, 6-diazaspiro [ 3.3)]Hept-2-yl) methanone (40 mg,0.17 mmol), potassium carbonate (55 mg,0.40 mmol), DMSO (1.5 mL) and oil bath at 90℃for 14h. The reaction solution was cooled to room temperature, then 5mL of water, ea (20 ml×2) was added to extract, the organic phase was washed with water (5 ml×3), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a silica gel column chromatography with eluent DCM-DCM/MeOH (v/v=10/1), to give a yellow solid, which was purified again by TLC to give 16mg of an off-white solid as a product, yield 12.33%. LC-MS: m/z=592.30 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝1.9Hz,1H),8.19(s,1H),8.15(d,J＝1.7Hz,1H),7.69(dd,J＝8.6,2.2Hz,1H),7.65(d,J＝8.7Hz,2H),7.10(d,J＝1.8Hz,1H),6.93(d,J＝8.7Hz,2H),6.43(d,J＝8.6Hz,1H),4.51(s,2H),4.43(s,3H),4.27(s,4H),4.14–4.06(m,3H),3.85(s,3H),3.68(d,J＝6.9Hz,1H),3.59(s,1H),3.14–3.01(m,3H),2.66(d,J＝10.1Hz,1H),1.91(s,1H),1.79(d,J＝9.6Hz,1H)。
Example 5:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Into a 100mL single-necked flask was charged hexahydropyrrolo [3,4-c ]]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (500 mg,2.36 mmol), 3-fluoro-2-methylbenzoic acid (550 mg,3.57 mmol) was dissolved by adding 10mL DCM, after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (903 mg,4.71 mmol) and 4-dimethylaminopyridine (580 mg,4.75 mmol) were added and reacted at room temperature for 15H. After stopping the reaction, the reaction mixture was directly concentrated, chromatographed on silica gel, eluting with DCM-DCM/MeOH (v/v=50/1), to give 620mg of a colorless viscous liquid as the product in 75.56% yield. LC-MS: m is m/z＝293.20[M-tBu+H] + ； 1 H NMR(400MHz,CDCl 3 )δ7.24–7.17(m,1H),7.05(d,J＝9.0Hz,1H),7.02–6.96(m,1H),3.89(dd,J＝12.2,8.0Hz,1H),3.70–3.50(m,3H),3.41(dd,J＝11.3,7.3Hz,1H),3.32(s,1H),3.23–3.08(m,1H),3.08–3.00(m,1H),2.97(d,J＝6.5Hz,1H),2.90–2.81(m,1H),2.23(d,J＝1.4Hz,3H),1.46(s,9H)。
Step 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone dihydrochloride
Into a 25mL single vial was added 5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (620 mg,1.78 mmol) was dissolved by adding EA (5 mL), HCl/EA (11 mL,44mmol,4 mol/L) was added and reacted at room temperature for 2H after the addition was completed. After the reaction is stopped, the reaction solution is directly concentrated to obtain white solid 410mg, namely the product, and the yield is 71.73%. LC-MS: m/z=249.20 [ m+h ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.30(dd,J＝13.3,7.8Hz,1H),7.20(t,J＝8.9Hz,1H),7.10(d,J＝7.4Hz,1H),3.73(dd,J＝12.6,7.8Hz,1H),3.55(dd,J＝12.7,4.0Hz,1H),3.44–3.21(m,3H),3.16–3.01(m,3H),3.00–2.87(m,2H),2.15(d,J＝1.6Hz,3H)。
Step 3:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (20 mg,0.05271mmol, intermediate 2), (hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone dihydrochloride (30 mg,0.1053 mmol), potassium carbonate (51 mg,0.36900 mmol), DMSO (1.5 mL) and oil bath at 90℃for 15H. After stopping the reaction, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography, eluent DCM-DCM/MeOH (v/v=10/1), to give 16mg of a yellow solid as a product, yield 49.95%. LC-MS: m/z=608.40 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝2.0Hz,1H),8.20(s,1H),8.15(d,J＝1.7Hz,1H),7.70(dd,J＝8.7,2.3Hz,1H),7.23–7.17(m,1H),7.10(d,J＝1.7Hz,1H),7.06–6.99(m,2H),6.50(d,J＝8.7Hz,1H),4.45(s,1H),4.21–4.09(m,3H),4.00(dd,J＝12.7,7.7Hz,1H),3.87(dd,J＝10.5,7.8Hz,1H),3.80–3.65(m,5H),3.55–3.47(m,2H),3.41(dd,J＝10.9,4.2Hz,1H),3.19–3.11(m,4H),3.09–3.02(m,1H),2.71(d,J＝10.1Hz,1H),2.24(d,J＝1.0Hz,3H),1.96(d,J＝9.8Hz,1H),1.82(d,J＝9.8Hz,1H)。
Example 6:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) ethoxy) -4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
2, 6-diazaspiro [3.3] was added to a 50mL single vial]Heptane-2-carboxylic acid tert-butyl ester (500 mg,2.52 mmol), 3-fluoro-2-methylbenzoic acid (580 mg,3.76 mmol) was added DCM followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (480 mg,5.11 mmol), 4-dimethylaminopyridine (636 mg,5.21 mmol) and reacted at room temperature for 15h. After stopping the reaction, 5mL of saturated ammonium chloride solution was added to the reaction solution, DCM (40 ml×2) was extracted, the organic phase was washed with water (10 ml×2), dried over anhydrous sodium sulfate and chromatographed on a silica gel column, the eluent was DCM-DCM/meoh= (v/v=50/1), 480mg of a colorless liquid was obtained as the product, and the yield was 56.92%. LC-MS: m/z=335.20 [ m+h ] ] + ； 1 H NMR(400MHz,CDCl 3 )δ7.22–7.14(m,1H),7.09–6.98(m,2H),4.29(s,2H),4.11(d,J＝9.3Hz,2H),4.03(d,J＝4.7Hz,4H),2.28(d,J＝2.1Hz,3H),1.43(s,9H)。
Step 2: (3-fluoro-2-methylphenyl) (2, 6-diazaspiro [3.3] hept-2-yl) methanone
Into a 25mL single vial was added 6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (480 mg,1.43 mmol) was dissolved in DCM (5 mL), 0Trifluoroacetic acid (1.2 mL,16 mmol) was added at room temperature and after completion the reaction was carried out for 2.5h at room temperature. After the TLC detection reaction is finished, the reaction liquid is directly concentrated to obtain 330mg of liquid which is the product, and the yield is 98.12%. LC-MS: m/z=235.15 [ m+h ]] + . Step 4:6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-yl) ethoxy) -4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [ 3.3)]Heptane-2-yl) pyridin-3-yl pyrazolo [1,5-a ]]Pyridine-3-carbonitriles
Into a 5mL single vial was added 6- (2- ((1S, 4S) -2-oxa-5-azabicyclo [ 2.2.1)]Heptane-5-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (23 mg,0.06062mmol, intermediate 2), (3-fluoro-2-methylphenyl) (2, 6-diazaspiro [ 3.3)]Hept-2-yl) methanone (60 mg,0.26 mmol), potassium carbonate (55 mg,0.40 mmol), DMSO (1.5 mL) and oil bath at 90℃for 15h. After stopping the reaction, the reaction mixture was cooled to room temperature, 5mL of water was added, EA (20 mL. Times.2) was used for extraction, the organic phase was washed with water (5 mL. Times.3), saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography with DCM/MeOH (v/v=50/1-10/1) as eluent, to give 14mg of an off-white solid as the product, with a yield of 38.90%. LC-MS: m/z=594.25 [ m+h ] ] + ； 1 H NMR(400MHz,CDCl 3 )δ8.28(d,J＝2.1Hz,1H),8.19(s,1H),8.15(d,J＝2.0Hz,1H),7.69(dd,J＝8.6,2.3Hz,1H),7.23–7.18(m,1H),7.11–7.04(m,3H),6.42(d,J＝8.6Hz,1H),4.42(d,J＝11.7Hz,3H),4.30(d,J＝8.9Hz,2H),4.21(d,J＝8.7Hz,2H),4.15–4.07(m,5H),3.68(d,J＝8.1Hz,1H),3.60(s,1H),3.13–3.02(m,3H),2.66(d,J＝10.2Hz,1H),2.33(d,J＝2.0Hz,3H),1.91(d,J＝10.3Hz,1H),1.79(d,J＝9.3Hz,1H)。
Example 7:4- (6- (6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:6- (2, 3-Didimethylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
2, 6-diazaspiro [3.3] was added to a 50mL single vial]Heptane-2-carboxylic acid tert-butyl ester (500 mg,2.52 mmol), 2, 3-dimethylbenzoic acid (570 mg,3.80 mmol), DCM was added followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (962mg, 5.02 mmol), 4-dimethylaminopyridine (620 mg,5.07 mmol) and the reaction was carried out at room temperature for 23h. After stopping the reaction, 5mL of saturated ammonium chloride solution was added to the reaction mixture, the mixture was extracted with DCM (30 mL. Times.2), the organic phase was washed with water (10 mL. Times.2), dried over anhydrous sodium sulfate, and then chromatographed on silica gel column with DCM as eluent to give 360mg of a colorless liquid as the product in a yield of 43.20%. LC-MS: m/z=331.30 [ m+h ]] + 。
Step 2: (2, 3-dimethylphenyl) (2, 6-diazaspiro [3.3] heptane-2-yl) methanone
Into a 25mL single vial was added 6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3]Heptane-2-carboxylic acid tert-butyl ester (360 mg,1.090 mmol) was dissolved by adding DCM (4 mL), trifluoroacetic acid (0.8 mL,10 mmol) was added at 0deg.C and reacted at room temperature for 2h after completion. After the reaction is finished, the reaction solution is directly concentrated for the next step. LC-MS: m/z=231.10 [ m+h ] ] + 。
Step 3:4- (6- (6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (20 mg,0.049mmol, intermediate 3), 2, 3-dimethylphenyl) (2, 6-diazaspiro [ 3.3)]Heptan-2-yl) methanone (46 mg,0.20 mmol), potassium carbonate (45 mg,0.33 mmol), DMSO (1.0 mL) and oil bath at 90℃for 15h. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography with DCM/MeOH as eluent (v/v=10/1), to give 5mg of a yellow solid as a product in 16.46% yield. LC-MS: m/z=616.30 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝1.8Hz,1H),8.19(s,2H),7.69(dd,J＝8.6,2.1Hz,1H),7.19(d,J＝6.5Hz,1H),7.15–7.08(m,3H),6.42(d,J＝8.6Hz,1H),4.40(s,2H),4.29(d,J＝8.8Hz,2H),4.25–4.19(m,4H),4.10(s,2H),3.73(s,1H),3.61(d,J＝4.4Hz,1H),3.09(t,J＝5.3Hz,2H),2.73(d,J＝14.3Hz,2H),2.30(s,6H),2.25(d,J＝15.8Hz,2H),2.12–2.07(m,2H),1.66(d,J＝7.9Hz,2H)。
Example 8:4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2, 3-Dibenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Into a 25mL single-necked flask was added hexahydropyrrolo [3,4-c ]]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (500 mg,2.36 mmol), 2, 3-dimethylbenzoic acid (530 mg,3.53 mmol), was dissolved by adding DCM, after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (903 mg,4.71 mmol) and 4-dimethylaminopyridine (580 mg,4.7475 mmol) were added and reacted at room temperature for 17H. 10mL of water was added to the reaction solution, the aqueous phase was extracted with DCM (30 mL), the organic phases were combined and washed with water (10 mL. Times.2), dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column with PE-PE/EA (v/v=1/1) as eluent to give 660mg of colorless viscous liquid as the product in a yield of 81.37%. LC-MS: m/z=289.25 [ m-tbu+h ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.18(d,J＝7.3Hz,1H),7.12(t,J＝7.5Hz,1H),7.01(d,J＝7.3Hz,1H),3.69(dd,J＝12.3,7.7Hz,1H),3.50(s,1H),3.44–3.36(m,2H),3.31–3.24(m,1H),3.17(dd,J＝11.2,4.8Hz,1H),3.03(dd,J＝11.2,4.5Hz,1H),2.95–2.76(m,3H),2.25(s,3H),2.10(s,3H),1.39(s,9H)。
Step 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2, 3-dimethylphenyl) methanone dihydrochloride
A25 mL single vial was charged with 5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (330 mg,0.96 mmol) was dissolved by adding EA (3 mL), HCl/EA (2 mL,8mmol,4 mol/L) was added and reacted at room temperature for 1H after the addition was completed. In the reaction processWhite solid is separated out, the reaction liquid is directly concentrated after TLC detection of the raw materials is finished, the white solid is obtained, the white solid is dried in a vacuum drying oven at 60 ℃, 260mg of the product is obtained, and the yield is 85.54%. LC-MS: m/z=245.30 [ m+h ] ] + ； 1 H NMR(400MHz,DMSO-d 6 )δ7.18(d,J＝7.3Hz,1H),7.13(t,J＝7.5Hz,1H),7.03(d,J＝7.3Hz,1H),3.73(dd,J＝12.6,7.9Hz,1H),3.54(dd,J＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11–2.99(m,3H),3.00–2.86(m,2H),2.25(s,3H),2.12(s,3H)。
Step 3:4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (20 mg,0.049mmol, intermediate 3), (hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) (2, 3-dimethylphenyl) methanone dihydrochloride (27 mg,0.085 mmol), potassium carbonate (45 mg,0.33 mmol), DMSO (1.0 mL) and oil bath at 90℃for 16H. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography with DCM/MeOH as eluent (v/v=20/1), to give 10mg of a yellow solid as a product in a yield of 32.18%. LC-MS: m/z=630.30 [ m+h ]] + ； 1 H NMR：(400MHz,CDCl 3 )δ8.32(s,1H),8.20(s,1H),8.19(s,1H),7.71(d,J＝8.5Hz,1H),7.18–7.09(m,3H),7.05(d,J＝6.9Hz,1H),6.50(d,J＝8.7Hz,1H),4.24(t,J＝4.6Hz,2H),4.01(dd,J＝12.4,7.7Hz,1H),3.85(d,J＝7.8Hz,1H),3.80–3.71(m,3H),3.62(s,1H),3.51(d,J＝5.6Hz,2H),3.41(d,J＝6.8Hz,1H),3.20–3.00(m,6H),2.74(d,J＝15.1Hz,2H),2.28(s,3H),2.23(s,1H),2.21(s,3H),2.10(s,2H),1.67(d,J＝7.8Hz,2H)。
Example 9:6- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) ethoxy) -4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo 1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2-chloroethyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
Into a 25mL single vial was added 2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (400 mg,2.02 mmol) was added CH 3 CN (6 mL), potassium carbonate (1.0 g,7.2 mmol), 1-bromo-2-chloroethane (0.5 mL,6 mmol) was added and reacted at room temperature for 17h after the addition was completed. After the reaction is finished, the reaction liquid is filtered, filter cake EA is washed for a plurality of times, filtrate is concentrated and subjected to silica gel column chromatography, and eluent is: DCM/MeOH (v/v=20/1) gave 130mg as a colorless liquid as the product in 24.71% yield. LC-MS: m/z=261.20 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ4.30(d,J＝49.6Hz,1H),3.51(t,J＝6.9Hz,3H),3.17(t,J＝8.7Hz,1H),3.01(dd,J＝26.6,9.4Hz,1H),2.91(t,J＝6.6Hz,2H),2.60(dd,J＝53.6,9.4Hz,1H),1.91–1.79(m,2H),1.76–1.67(m,1H),1.46(s,9H)。
Step 2:5- (2- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
A25 mL single vial was charged with 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] sequentially]Pyridine-3-carbonitrile (50 mg,0.20 mmol), potassium carbonate (85 mg,0.62 mmol), 5- (2-chloroethyl) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-carboxylic acid tert-butyl ester (130 mg,0.50 mmol), DMF (2.5 mL) was reacted at 80℃for 5h. After the reaction was stopped, the reaction mixture was cooled to room temperature, 10mL of water was added, ea (40 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a silica gel column chromatography with eluent DCM/MeOH (v/v=10/1) to give 70mg as the product in 74.37% yield. LC-MS: m/z=479.30 [ m+h ] ] + 。
Step 3:5- (2- ((3-cyano-4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
In a 10mL single vial was added 5- (2- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1, 5-a)]Pyridin-6-yl) oxy) ethyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (70 mg,0.1463 mmol), (hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone dihydrochloride (55 mg,0.1712mmol, example 5, step 2), potassium carbonate (85 mg,0.61501 mmol), DMSO (1.5 mL) was reacted for 24H at 90℃in an oil bath. After cooling the reaction to room temperature, 5mL of water, EA (20 mL. Times.2) was added for extraction, the organic phase was washed with water (5 mL. Times.3), saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a silica gel column chromatography with DCM/MeOH (v/v=10/1) as eluent, affording 70mg of a yellow solid as the product in 67.70% yield. LC-MS: m/z=707.15 [ m+h] + ； 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝2.2Hz,1H),8.19(s,1H),8.13(d,J＝1.9Hz,1H),7.70(dd,J＝8.7,2.4Hz,1H),7.21–7.18(m,1H),7.10(d,J＝1.9Hz,1H),7.04–7.00(m,2H),6.50(d,J＝8.7Hz,1H),4.12–4.07(m,2H),4.03–3.97(m,1H),3.94–3.84(m,2H),3.82–3.69(m,3H),3.60(s,2H),3.53–3.48(m,3H),3.45–3.39(m,2H),3.22–3.13(m,4H),3.05(s,3H),2.24(d,J＝1.6Hz,3H),1.46(s,9H)。
Step 4:6- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) ethoxy) -4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo 1,5-a ] pyridine-3-carbonitrile
In a 10mL single vial was added 5- (2- ((3-cyano-4- (6- (5- (3-fluoro-2-methylbenzoyl)) hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) pyridin-3-yl pyrazolo [1,5-a ]]Pyridin-6-yl) oxy) ethyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (70 mg,0.10 mmol) was dissolved by adding EA (2 mL), HCl/EA (0.3 mL,1mmol,4 mol/L) was added under ice, and the mixture was allowed to spontaneously warm to room temperature for 30min. After TLC detection of the completion of the reaction of the starting materials, the reaction mixture was directly concentrated, and then 2mL of methanol was added for dissolution, followed by addition of potassium carbonate (200 mg,1.45 mmol) and stirring at room temperature for 40min to liberate the base. The reaction was directly concentrated on silica gel column chromatography eluting with DCM/MeOH (v/v=10/1) to give a yellow solid which was again purified by TLC to give 24mg of the product as a pale yellow solid in 39.94% yield. LC-MS: m/z=607.30 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝2.1Hz,1H),8.19(s,1H),8.12(d,J＝1.7Hz,1H),7.69(dd,J＝8.7,2.3Hz,1H),7.20(dd,J＝13.1,7.7Hz,1H),7.07(d,J＝1.8Hz,1H),7.04–6.99(m,2H),6.49(d,J＝8.7Hz,1H),4.21(s,1H),4.09(t,J＝4.9Hz,2H),4.00(dd,J＝12.8,7.7Hz,1H),3.86(dd,J＝10.5,7.7Hz,1H),3.80–3.73(m,2H),3.72(s,2H),3.61(d,J＝9.8Hz,1H),3.51(dd,J＝10.9,6.4Hz,2H),3.41(dd,J＝11.0,4.2Hz,1H),3.23(d,J＝12.2Hz,1H),3.20–3.16(m,2H),3.15(s,2H),3.04(dd,J＝12.3,6.5Hz,2H),2.23(s,3H),2.09(d,J＝10.6Hz,1H),2.00(d,J＝10.5Hz,1H)。
Example 10:4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (25 mg,0.06mmol, intermediate 3), (hexahydropyrrolo [3, 4-c) ]Pyrrole-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone dihydrochloride (32 mg,0.10mmol, example 5, step 2), potassium carbonate (53 mg,0.38 mmol), DMSO (1.0 mL) and oil bath at 90℃for 13H. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a silica gel column chromatography with DCM/MeOH (v/v=20/1) as eluent, to give 5mg of a solid as a product in a yield of 12.79%. LC-MS: m/z=634.40 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝1.9Hz,1H),8.22(s,1H),8.21(s,1H),7.73(dd,J＝8.7,2.2Hz,1H),7.24–7.20(m,1H),7.12(s,1H),7.06–7.01(m,2H),6.52(d,J＝8.8Hz,1H),4.27(s,2H),4.02(dd,J＝12.7,7.7Hz,1H),3.91–3.86(m,1H),3.82–3.73(m,3H),3.53(dd,J＝10.1,6.2Hz,2H),3.43(dd,J＝11.0,4.2Hz,1H),3.18(dd,J＝11.0,5.1Hz,2H),3.14–3.10(m,2H),3.09–3.06(m,1H),2.77(d,J＝15.7Hz,2H),2.64(s,1H),2.29(s,1H),2.26(s,4H),2.11(s,2H),1.69(d,J＝8.0Hz,2H)。
Example 11:4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (27 mg,0.067mmol, intermediate 3), (hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -yl) (4-methoxyphenyl) methanone dihydrochloride (35 mg,0.11mmol, example 2, step 2), potassium carbonate (61 mg,0.44 mmol), DMSO (1.5 mL) was reacted for 17H at 90℃in an oil bath. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water, ea (20 ml×2) was added to extract, the organic phase was washed with water (5 ml×3), and brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography with DCM/MeOH (v/v=20/1) as eluent, and after the product was obtained, TLC was again purified to give 12mg of yellow solid as the product in a yield of 28.52%. LC-MS: m/z=632.30 [ m+h ] ] + ； 1 H NMR(400MHz,CDCl 3 )δ8.32(d,J＝1.8Hz,1H),8.20(d,J＝7.0Hz,2H),7.71(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝8.6Hz,2H),7.10(d,J＝1.5Hz,1H),6.91(d,J＝8.6Hz,2H),6.50(d,J＝8.8Hz,1H),4.24(t,J＝5.2Hz,2H),4.02(s,1H),3.84(s,3H),3.73(s,1H),3.66(s,4H),3.61(d,J＝3.9Hz,1H),3.51(s,3H),3.11–3.08(m,2H),2.74(d,J＝14.7Hz,2H),2.25(d,J＝15.8Hz,2H),2.09(d,J＝5.3Hz,2H),1.67(d,J＝7.9Hz,2H),1.29(s,2H)。
Example 12:4- (6- (6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
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5mL Single Vial 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (32 mg,0.079mmol, intermediate 3), (4-methoxyphenyl) (2, 6-diazaspiro [ 3.3)]Heptan-2-yl) methanone (104 mg,0.45mmol, example 4 step 2), potassium carbonate (70 mg,0.51 mmol), DMSO (1.5 mL) and oil bath at 90℃for 16h. After the reaction was completed, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×4), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a silica gel column chromatography, eluent DCM/MeOH (v/v=10/1), and after the product was obtained, 15mg of a yellow solid was obtained after TLC purification again, and the yield was 30.46%. LC-MS: m/z=618.30 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝1.9Hz,1H),8.21–8.17(m,2H),7.69(dd,J＝8.6,2.2Hz,1H),7.64(d,J＝8.7Hz,2H),7.09(d,J＝1.8Hz,1H),6.92(d,J＝8.7Hz,2H),6.42(d,J＝8.6Hz,1H),4.46(d,J＝39.3Hz,4H),4.26(s,3H),4.22(t,J＝5.5Hz,2H),3.85(s,3H),3.65(s,3H),3.08(t,J＝5.5Hz,2H),2.71(d,J＝13.4Hz,2H),2.24(d,J＝15.8Hz,2H),2.10–2.05(m,2H),1.65(d,J＝7.9Hz,2H)。
Example 13:4- (6- (5- (4-methoxybenzoyl) -2, 5-diazabicyclo [2.2.1] oct-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (4-Methoxybenzoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
To a 25mL single port flask was added tert-butyl 2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (300 mg,1.51 mmol), 4-methoxybenzoic acid (695 mg,4.57 mmol), DCM (6 mL) was added to dissolve it, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (560 mg,3.08 mmol), 4-dimethylaminopyridine (375 mg,3.07 mmol) and the reaction was carried out at room temperature for 21h. After stopping the reaction, 5mL of saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with DCM (20 mL. Times.2), the organic phases were combined and washed with water (5 mL. Times.2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column with DCM/MeOH (v/v=50/1) as eluent to give 400mg of a white solid as the product in 79.53% yield.
LC-MS：m/z＝333.25[M+H] + ； 1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝7.8Hz,2H),6.93(d,J＝7.9Hz,2H),4.55–4.43(m,1H),3.84(s,3H),3.69(d,J＝11.2Hz,1H),3.61–3.46(m,2H),3.40(s,1H),1.90(s,1H),1.83(d,J＝9.9Hz,2H),1.49(s,6H),1.43(s,3H)。
Step 2: (2, 5-diazabicyclo [2.2.1] hept-2-yl) (4-methoxyphenyl) methanone hydrochloride
Into a 25mL single vial was added 5- (4-methoxybenzoyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (200 mg,0.60 mmol) was dissolved by adding EA (3 mL), HCl/EA (2.1 mL,8.4mmol,4 mol/L) was added, and the mixture was reacted at room temperature for 4 hours after the completion of the addition. After the reaction is stopped, the reaction solution is directly concentrated to obtain 130mg of white solid which is the product, and the yield is 95.87%. LC-MS: m/z=233.20 [ m+h ] ] + 。
Step 3:4- (6- (5- (4-methoxybenzoyl) -2, 5-diazabicyclo [2.2.1] oct-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (27 mg,0.067mmol, intermediate 3), (2, 5-diazabicyclo [ 2.2.1)]Hept-2-yl) (4-methoxyphenyl) methanone hydrochloride (30 mg,0.1116 mmol), potassium carbonate (55 mg,0.40 mmol), DMSO (1.5 mL) and oil bath at 90℃for 29h. After the reaction, the reaction solution was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×4), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography, eluent DCM/MeOH (v/v) =10/1, and after the product was obtained, the product was purified again by TLC to give 5mg of an off-white solid as a product, yield 12.15%. LC-MS: m/z=618.25 [ m+h ]] + ； 1 H NMR：(400MHz,CDCl 3 )δ8.28(d,J＝30.5Hz,1H),8.20(s,2H),7.70(d,J＝12.5Hz,1H),7.52(s,2H),7.10(d,J＝17.3Hz,1H),6.91(dd,J＝31.2,7.5Hz,2H),6.50(dd,J＝37.0,8.9Hz,1H),4.24(s,2H),3.84(d,J＝15.9Hz,4H),3.71(s,2H),3.61(d,J＝4.7Hz,2H),3.09(s,2H),2.73(d,J＝15.6Hz,2H),2.25(d,J＝15.9Hz,2H),2.07(s,3H),2.03(s,2H),1.66(d,J＝8.0Hz,2H),0.88(t,J＝6.6Hz,2H)。
Example 14:4- (6- (5- (3-fluoro-2-methylbenzoyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (3-fluoro-2-methylbenzoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
Into a 25mL single vial was added 2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (300 mg,1.51 mmol), 3-fluoro-2-methylbenzoic acid (463 mg,3.00 mmol) was added and dissolved in DCM (6 mL), after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (576 mg,3.00 mmol), 4-dimethylaminopyridine (803 mg,2.97 mmol) was added and reacted at room temperature for 17h after the addition. After stopping the reaction, 5mL of saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with DCM (20 mL. Times.2), the organic phases were combined and washed with water (5 mL. Times.2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column with DCM/MeOH (v/v=50/1) as eluent to give 160mg of a colorless liquid as the product in a yield of 31.62%. LC-MS: m/z=335.20 [ m+h ]] + 。
Step 2:2, 5-diazabicyclo [2.2.1] hept-2-yl (3-fluoro-2-methylphenyl) methanone hydrochloride
Into a 25mL single vial was added 5- (3-fluoro-2-methyl-benzoyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (160 mg,0.48 mmol) was dissolved by adding EA (3 mL), and after completion, HCl/EA (1.6 mL,6.4mmol,4 mol/L) was added and reacted at room temperature for 1.5h. After the reaction is stopped, the reaction solution is directly concentrated to obtain 125mg of white solid which is the product with the yield of 96.51 percent. LC-MS: m/z=235.10 [ m+h ] ] + 。
Step 3:4- (6- (5- (3-fluoro-2-methylbenzoyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (25 mg,0.062 mmol), 2, 5-diazabicyclo [2.2.1]Hept-2-yl (3-fluoro-2-methylphenyl) methanone hydrochloride (55 mg,0.2032mmol, intermediate 3), potassium carbonate (54 mg,0.39 mmol), DMSO (1.5 mL) and oil bath at 90℃for 18h. After the reaction is finished, the reaction solution is cooled to room temperature, 5mL of water is added, EA (20 mL multiplied by 2) is extracted, an organic phase is washed with water (5 mL multiplied by 4), saturated saline is washed with water (5 mL multiplied by 2), anhydrous sodium sulfate is dried and filtered, filtrate is decompressed and concentrated to silica gel column chromatography, eluent is DCM/MeOH (v/v=10/1), and after the product is obtained, 14mg of pale yellow solid is obtained after TLC purification, and the yield is 36.63%. LC-MS: m/z=620.30 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝25.2Hz,1H),8.25–8.14(m,2H),7.72(dd,J＝15.1,5.9Hz,1H),7.25–7.15(m,1H),7.14–6.92(m,3H),6.49(t,J＝9.6Hz,1H),5.05(d,J＝13.3Hz,1H),4.24(d,J＝5.5Hz,2H),3.78(s,1H),3.70(d,J＝9.5Hz,1H),3.62(d,J＝7.7Hz,1H),3.48(d,J＝40.1Hz,1H),3.27(dd,J＝24.6,9.7Hz,1H),3.09(dd,J＝10.5,5.2Hz,2H),2.73(d,J＝15.7Hz,2H),2.30–2.19(m,4H),2.10(s,3H),2.04(s,2H),1.67(d,J＝8.0Hz,2H),0.87(d,J＝10.0Hz,2H)。
Example 15:4- (6- (5- (2, 3-dimethylbenzoyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2, 3-Dibenzoyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
Into a 25mL single vial was added 2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (300 mg,1.51 mmol), 2, 3-dimethylbenzoic acid (463 mg,3.08 mmol) was added and dissolved in DCM (6 mL), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimideAmine hydrochloride (576 mg,3.00 mmol), 4-dimethylaminopyridine (803 mg,2.97 mmol) was reacted at room temperature for 17h after the addition. After stopping the reaction, 5mL of saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with DCM (20 mL. Times.2), the organic phases were combined and washed with water (5 mL. Times.2), dried over anhydrous sodium sulfate, and then chromatographed on a silica gel column with DCM/MeOH (v/v=50/1) as eluent to give 210mg of a colorless liquid as the product in 42.00% yield. LC-MS: m/z=331.30 [ m+h ]] + 。
Step 2:2, 5-diazabicyclo [2.2.1] hept-2-yl (2, 3-dimethylphenyl) methanone hydrochloride
Into a 25mL single vial was added 5- (2, 3-dimethylbenzoyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (210 mg,0.64 mmol) was dissolved by adding EA (3 mL), HCl/EA (2.4 mL,9.6mmol,4 mol/L) was added, and the mixture was reacted at room temperature for 1h after the addition was completed. After the reaction is stopped, the reaction solution is directly concentrated to obtain 160mg of white solid which is the product with the yield of 94.35 percent. LC-MS: m/z=231.15 [ m+h ] ] + 。
Step 3:4- (6- (5- (2, 3-dimethylbenzoyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -6- (2- (3-oxo-8-azabicyclo [3.2.1] oct-8-yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Into a 5mL single vial was added 4- (6-fluoro-3-yl) -6- (2- (3-oxo-8-azabicyclo [ 3.2.1)]Octane-8-yl) ethoxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (26 mg,0.064mmol, intermediate 3), 2, 5-diazabicyclo [2.2.1]Hept-2-yl (2, 3-dimethylphenyl) methanone hydrochloride (120 mg,0.45 mmol), potassium carbonate (52 mg,0.38 mmol), DMSO (1.5 mL) and oil bath at 90℃for 16.5h. After the reaction was completed, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×4), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography with DCM/MeOH as eluent (v/v=10/1), to give 13mg of a yellow solid as a product in a yield of 32.92%. LC-MS: m/z=616.35 [ m+h ]] + ； 1 H NMR(400MHz,CDCl 3 )δ8.29(dd,J＝24.3,1.9Hz,1H),8.20(t,J＝4.8Hz,2H),7.74–7.65(m,1H),7.22–7.05(m,4H),6.49(t,J＝9.6Hz,1H),5.03(d,J＝17.0Hz,1H),4.23(dd,J＝11.4,5.7Hz,2H),3.78(s,1H),3.70(d,J＝10.6Hz,1H),3.53–3.40(m,1H),3.25(dd,J＝24.9,9.7Hz,1H),3.09(dd,J＝10.8,5.4Hz,2H),2.72(d,J＝16.1Hz,2H),2.32(s,2H),2.27(s,1H),2.25(s,2H),2.23(s,3H),2.10(s,1H),2.07(s,2H),2.02(s,2H),1.66(d,J＝8.1Hz,2H),0.88(dd,J＝9.5,5.9Hz,2H)。
The target compounds (223) - (227) of examples 223-227, the target compounds (19) - (85) of examples 19-85, the target compounds (87) - (90) of examples 87-90, the target compound (189) of example 189, the target compound (195) of example 195, the target compounds (202) - (206) of examples 202-206, the target compounds (208) - (210) of examples 208-210, the target compounds (215) - (216) of examples 215-216, the target compound (218) of example 218, the target compound (220) of example 220 were prepared by reference to the synthetic route of example 1 or synthetic scheme 1, the specific structures and characterization data are as described in table 1 below, using the appropriate starting materials:
TABLE 1
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The specific structures and characterization data for the preparation of the target compounds (91) - (92) of examples 91-92, the target compounds (94) - (107) of examples 94-107, the target compounds (111) - (122) of examples 111-122, the target compounds (126) - (135) of examples 126-135, the target compounds (139) - (142) of examples 139-142, the target compounds (150) - (170) of examples 150-170, the target compounds (173) - (177) of examples 173-177, the target compounds (186) - (188) of examples 186-188, the target compounds (190) - (194) of examples 190-194, the target compounds (196) - (201) of examples 196-201, the target compound (207) of example 207, the target compounds (211) - (214) of examples 211-221, and the synthetic route of example 1 are as described in table 2 below, using appropriate starting materials.
TABLE 2
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The target compounds (228) of example 228, the target compounds (16) to (18) of example 16 to 18, the target compound (86) of example 86, the target compound (93) of example 93, the target compounds (108) to (110) of example 108 to 1110, the target compounds (123) to (125) of example 123 to 125, the target compounds (136) to (138) of example 136 to 138, the target compounds (143) to (149) of example 143 to 149, the target compounds (171) to (173) of example 171 to 173), the target compounds (178) to (185) of example 178 to 185, the target compound (217) of example 217, the target compound (219) of example 222, and the target compound (222) of example 222 were prepared by the synthetic route referring to example 2 or synthetic scheme 2 using appropriate starting materials, the specific structures and characterization data are as described in the following table 3:
TABLE 3 Table 3
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Biological Activity test examples:
test example 1:
1. the purpose of the experiment is as follows:
test series of compounds for inhibitory Activity against 2 kinases, ret wt, ret V804M, by HTRF method and determine IC 50 Values.
2. The experimental reagents and consumables used were as follows:
1)HTRF KinEASE-TK kit(Cisbio，62TK0PEC)
2)Ret wt(Invitrogen，PV3082)
3)Ret V804M(Signalchem，R02-12GG-10)
4)MgCl2(Sigma，M1028)
5)ATP(Promega，V910B)
6)DTT(Invitrogen，P2325)
7)DMSO(Sigma，D8418)
8)384-well plate,white,low volume,round-bottom(Greiner，784075)
9)384-Well Polypropylene microplate,Clear,Flatt Bottom,Bar Code(Labcyte，P-05525-BC)
10)96-well polypropylene plate(Nunc，249944)
11)Plate shaker(Thermo，4625-1CECN/THZ Q)
12)Centrifuge(Eppendorf，5810R)
13)Envision 2104multi-label Reader(PerkinElmer，2104-10-1)
14)Echo(Labcyte，550)
3. experimental procedure
3.1 preparation of 1x kinase reaction buffer:
1 volume of 5X kinase reaction buffer and 4 volumes of water; 5mM MgCl2;1mM DTT;1mM MnCl2.
3.2 transfer of 10nl of diluted compound per well with an Echo 550 reaction plate (784075, greiner);
3.3 the reaction plate was sealed with a sealing plate membrane and centrifuged at 1000g for 1 min.
3.4 preparation of 2X kinase with 1X enzyme reaction buffer.
3.5 mu.l kinase (formulated in step 3) was added to each well in the reaction plate. 1000g of the plate is sealed by a sealing plate membrane and centrifuged for 30 seconds, and the plate is placed at room temperature for 10 minutes.
3.6 preparation of 4 XTK-substrate-biotin and 4 XATP with 1 Xenzyme reaction buffer, mixing well, and adding 5. Mu. l K-substrate-biotin/ATP mixture to the reaction plate.
3.7 sealing the plates with sealing plate film 1000g and centrifuging for 30 seconds, reacting for 40 minutes at room temperature.
3.8 4 XSa-XL 665 (250 nM) was formulated in HTRF detection buffer.
3.9 mu.l of Sa-XL 665 and 5. Mu.l of TK-anti-Cryptate were added per well and centrifuged at 1000g for 30 seconds and reacted at room temperature for 1 hour.
3.10 fluorescence signals at 615nm (Cryptate) and 665nm (XL 665) were read with Envision 2104.
4. Data analysis
4.1 calculating the Ratio per well (ratio_665/615 nm)
4.2 inhibition was calculated as follows:
average of CEP-32496 readings from all positive control wells
Mean value of DMSO well readings for all negative control wells
Wherein, the chemical name of CEP-32496 is: n- [3- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl ] -N' - [5- (2, 2-trifluoro-1, 1-dimethylethyl) -3-isoxazolyl ] urea.
4.3 calculation IC 50 And plotting inhibition curves of the compounds:
IC of the compound was obtained using the following nonlinear fitting equation 50 (half inhibition concentration): data analysis was performed using Graphpad 6.0 software.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×Hill Slope))
Log of compound concentration Y, inhibition (% inhibition)
5. The experimental results are shown in table a:
table A kinase inhibitory Activity of the Compounds of the invention
As can be seen from Table A, the compounds of the present invention have a good inhibitory effect on Ret wt, and in addition, the compounds of the present invention have a good inhibitory effect on Ret V804M.
In addition to the activity of the compounds of the invention in Table A, other compounds of the invention also have good Ret kinase inhibitory activity.
Test example 2:
1. the purpose of the experiment is as follows:
test compounds were tested for 50% inhibition of cell proliferation concentration (IC) in a range of tumor cells using CTG method 50 )。
2. The experimental reagents and test samples used were as follows:
1)CellTiter-Glo(CTG)(Promega)
2) RPMI medium (Gibco)
3) FBS (fetal bovine serum) (Gibco)
4)DMSO(Sigma)
5) Double antibody (Gibco)
6) 96 well cell culture plate, white wall and impermeable bottom (Corning)
7) BAF3 (purchased from Shanghai Mingjin organism)
8) BAF3-KIF5B-RET-WT (Steady transfer cell line, constructed by the pharmacology division of the east Guangdong optical pharmaceutical Co., ltd.)
3. The experimental steps are as follows:
1) Cell seeding
Cells in exponential growth phase, BAF3 and BAF3-KIF5B-RET-WT, were collected and viable Cell counted using a Vi-Cell XR cytometer. The cell suspension was adjusted to the corresponding concentration with RPMI complete medium (89% rpmi+10% fbs+1% diabody). mu.L of the cell suspension was added to each well in a 96-well cell culture plate at final cell concentrations of 2000 cells/well and cell cells/well, respectively.
2) Dosing treatment
a, preparing working solution: each test compound was dissolved in DMSO to a final concentration of 10mM stock solution. Serial 3X dilutions were prepared using stock and RPMI complete medium (89% rpmi+10% fbs+1% diabody) for a total of 10 working solutions, each with a final DMSO concentration of 0.1%.
b cell dosing: after the cells are incubated overnight, 10ul of working solution with 10 gradient concentrations are sequentially added, and the cells are placed in a 37 ℃ and 5% CO2 incubator for incubation for 72 hours; negative controls were also set up without compound plus cells.
3) Read plate detection
After 72 hours of drug treatment, 50. Mu.l (1/2 of the culture volume) of CTG solution, which had been previously thawed and equilibrated to room temperature, was added to each well according to the CTG protocol, mixed with a microplate shaker for 2 minutes, and after 10 minutes at room temperature, the fluorescence signal value was measured using a multifunctional microplate reader.
4) Data analysis
Cell viability was expressed as: vsample/Vvehicle control x% calculation. Where Vsample is the reading for the drug-treated group and Vvehicle control is the average of the solvent control group. Using GraphPad Prism 5.0 software, an S-type dose-survival curve was drawn using a nonlinear regression model and IC was calculated 50 Values, experimental results are shown in table B.
TABLE B in vitro cell Activity of the Compounds of the invention
As can be seen from Table B, the compounds of the present invention also have good inhibitory effects on BAF3 cells transfected with the KIF5B gene.
In the description of the present specification, the descriptions of the terms "one embodiment," "some embodiments," "some implementations," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that changes, modifications, substitutions and variations may be made therein by those of ordinary skill in the art without departing from the spirit and scope of the invention, which is defined by the appended claims and their equivalents.

Claims (13)

1. A compound which is a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
wherein,
X 1 、X 2 、X 3 、X 4 and X 5 Each independently is CR 4 Or N;
y is O;
t is C 1-6 An alkylene group;
ring G is a 6-12 membered bridged heterocyclyl;
q is 0 or 1;
R a d, oxo, methyl, ethyl, propyl, butyl, methoxy or ethoxy;
e is a bond;
ring a is of the sub-structural formula:
wherein each Z 1a And Z 2a Independently NH;
each Z is 3a And Z 7a Is independently CH;
Z 4a is O or NH;
each Z is 5a And Z 6a Independently CH 2 O or NH;
each m and t is independently 0, 1 or 2;
each n and t1 is independently 0 or 1;
wherein each sub-structural formula of ring A is independently optionally substituted with 1 or 2 groups selected from F, cl, br, OH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Substituted by a substituent of hydroxyalkyl;
q is-CH 2 -or- (c=o) -;
m is pyridyl, pyrimidinyl, pyrazinyl or phenyl; and M is optionally selected from D, F, cl, CN, OH, CF by 1, 2 or 3 3 、CHCl 2 、CHF 2 、CH 2 F、CF 3 CH 2 A substituent selected from the group consisting of trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, t-butoxy, methyl, ethyl, n-propyl and isopropyl;
R 1 h, D, CN, F, cl, br, methyl, ethyl or cyclopropyl;
R 4 h, D, F, cl, br, methyl, ethyl, n-propyl, methoxy or ethoxy.
2. The compound according to claim 1, wherein,
t is-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -or- (CH) 2 ) 6 -。
3. The compound according to claim 1, wherein,
ring G is of the sub-structural formula:
wherein,
each Z is 1 Independently N; and
each Z is 2 Independently CH 2 、C＝O、NH、O、S, S = (O) or s= (O) 2 。
4. The compound according to claim 1, wherein,
ring G is of the sub-structural formula:
R a d, oxo, methyl, ethyl, propyl, butyl, methoxy or ethoxy.
5. The compound according to claim 1, wherein,
ring a is of the sub-structural formula:
wherein each sub-structural formula of ring A is independently optionally substituted with 1 or 2 groups selected from F, cl, br, OH, oxo, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 A hydroxymethyl group or a 2-hydroxyethyl group.
6. The compound of claim 1 having the structure of formula (I-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt of the structure of formula (I-1),
wherein,
ring A1 is of the sub-structural formula:
wherein each Z 1a And Z 2a Independently NH;
and each sub-structural formula of ring A1 is independently optionally substituted with 1, 2, 3 or 4 groups selected from F, cl, br, OH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 The substituent of the hydroxyalkyl group is substituted.
7. The compound according to claim 6, wherein,
ring A1 is of the sub-structural formula:
wherein each sub-structural formula of ring A1 is independently optionally substituted with 1 or 2 groups selected from F, cl, br, OH, oxo, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 A hydroxymethyl group or a 2-hydroxyethyl group.
8. The compound of claim 1 having the structure of formula (I-2), or a stereoisomer, tautomer, or pharmaceutically acceptable salt of the structure of formula (I-2),
wherein each Z 1 And Z 2 Independently N;
Z 3a and Z 7a Is independently CH;
each m and t is independently 0, 1 or 2;
each n and t1 is independently 0 or 1;
wherein the method comprises the steps ofOptionally by 1 or 2 groups selected from F, cl, br, OH, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 The substituent of the hydroxyalkyl group is substituted.
9. The compound according to claim 8, wherein,
the following sub-structural formula is shown as follows:
wherein the method comprises the steps ofIs independently optionally substituted with 1 or 2 groups selected from F, cl, br, OH, oxo, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3 A hydroxymethyl group or a 2-hydroxyethyl group.
10. The compound of claim 1 having one of the following structures, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
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11. a pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10, and a pharmaceutically acceptable adjuvant.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the prevention or treatment of RET related diseases.
13. Use according to claim 12, wherein the RET related disease comprises cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
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